The most interesting paper I’ve read in the past 5 years — Introduction and allegro

Have a look at Nature vol. 495 pp. 111 – 115 ’13, and the accompanying editorial (ibid. pp. 57 – 58) and see if you can find out why I think it is so fascinating. It has to do with my background and interests over the last 50+ years which are unlikely to be completely the same as the readers of this blog.

This post will be about computers, and how they can be completely understood in terms of their components (because humans constructed them). The next will be a boiled down version of the 6 articles https://luysii.wordpress.com/category/molecular-biology-survival-guide/.

Well, for nearly all my professional career 1962 – 2000 I was a neurologist and neurologists must deal with the brain and attempt to understand how it works (which we still don’t). The brain (and mind) has always been interpreted using the dominant technology of the day.

Freud (1856 – 1939) formulated his work when steam power was widely known and used. He studied with most eminent neurologist of the time (Charcot) after getting his M. D. His conception of the mind and it’s pathology had to do with powerful urges and the way they were channeled through the pipes of the psyche. In particular, traumatic events if allowed to build up in the system, could create pressures and wreck the psychiatric machinery. Hence the emphasis on discovering the blockages and releasing them before the steam engine exploded into pathology. This approach is alive and well today — can you say PTSD ?

Presently the brain is thought of in terms of the current dominant technology — the computer. It runs programs. Use of this analogy goes back to the dawn of the computer age way before they became widespread. John von Neumann who invented the stored program computer, in which programs and data looked the same, wrote “The Computer and the Brain” before his death in 1957.

So as a neurologist (and general techie) I was fascinated with them when they came out for the general public. Obviously, they could be completely understood because we created them. I bought an alpha Micro (long gone) which was the fruits of some engineers who worked at Digital Equipment Compancy (DEC — long gone), which was sold to Compaq (also long gone), back in the early 80′s.

Don’t laugh at what I bought; it was state of the art at the time. It had 64 kiloBytes of memory, of which 32 kiloBytes was taken up by the operating system, and the other 32 was used for programs. I read about the logic behind computers, and quickly realized that everything important happened inside the ALU (Arithmetic and Logical Unit), which had places to store data (registers) and a place to store one instruction (another register called the instruction pointer). The instructions were 16 bits (2 bytes long). The disc was state of the art at the time — all of 80 megaBytes — it looked (and sounded) like a washing machine, with removable platters which looked like giant thick frisbies.

I’d read up on how registers could be built up from logic gates (AND, OR, NOR, NAND). So, on paper, I built logical registers from these elements. I had a clock as well (a black box) which could send signals to the gates coordinating things. I quickly understood that for the simplest instruction == Add register A to register B, further instructions were necessary — this is the microcode — e.g. move register A to the ALU, open register B, use it as input along with the instruction code for Add, to perform the addition, then store it someplace.

Then after understanding how the instructions operated, I wrote a program to take the ones and zeros of the instructions of the operating system, and turn them into something readable e.g. 0110101000001111 into ADD A, B. This allowed me to see how instructions were turned into a functioning machine.

Why do it? Well, it was interesting, and at the end of all this an understanding of how computers work could be had. Clearly the output depended on the internal structure of the computer (which didn’t change) and the program fed into it (which did). Once you understood the structure of the computer and the language of the instructions, all you needed to understand its output was the program (e.g. the code).

As all this was going on, people were deciphering the chemical nature of the genetic code. Know the sequence of nucleotides in the code and you’d know everything was the zeitgeist. By an enormous effort the first sequence of an organism became available in 1977 — it was of a DNA virus PhiX-179. It had all of 5,386 base pairs and was a huge amount of work. The human genome project was decades away.

This sort of genetic hubris is the subject of the next post in the series. If you’ve read the paper, can you now see why I find it so fascinating? Stay tuned.

That’s why they’re called the blues

A fascinating paper. [ Proc. Natl. Acad. Sci. vol. 110 pp. 8836 - 8841 '13 ] 18 selections of classical orchestral music by Bach, Mozart and Brahms were played to Americans and Mexicans. People from both cultures chose colors suggested by the music the same way. Faster music in the major mode produces color choices which are more saturated, lighter and yellower. Slower, minor music produces the opposite pattern (desaturated, darker and BLUER).

That’s why they’re called the blues.

Although I’m a lifelong musician (piano) music has never suggested any colors to me at all.

The New Clayden pp. 852 – 876

This is a great chapter, showing what I think are state of the art stereochemical control mechanisms in actual natural product syntheses in the literature.  It’s exactly why I’m reading the new Clayden before trying to read blogs like Totally Synthetic (to get up to speed with what’s going on now after reading the first edition). Probably the syntheses presented at chapter’s end are at the graduate level, but they use nothing that hasn’t already been discussed.

One of my musician friends asked, what I was going to use the math I’m reading for.  We’d just finished playing a great Dvorak piano trio and I told her the same thing we used the trio for.   To me, at least, it’s all the same.  I get esthetic kicks from music, math and clever organic syntheses.  The quality of esthetic pleasure is differs among the three, but it’s esthetic nonetheless.

p. 854 — “For a stereospecific alkene transformation, choose the right geometry of the starting material to get the right diasteroisomer of the product.   Don’t try to follow any ‘rules’ just work through the mechanism.”   Amen.  Let it be a sign on the doorposts of thy house.

p. 856 – 857 — I’m not trying to be obnoxious, but the discussion of prochirality seems to embed what is simple stereochemistry in a plethora of unnecessary terms. 

p 859 – 860 — It’s clear from the level of discussion of the conformations of phenyl methyl acetaldehyde, that the book was written by multiple authors.  This particular author is addressing the first time student (or at least this part is).  Nothing wrong with a little hand holding in an elementary textbook. 

p. 861 — ALthough Dolastatin is said to be ‘one of the most powerful anticancer agents known’  it isn’t in clinical use.  It inhibits mitosis, so probably side effects kept it away from the bedside. 

pp. 858 – 865 — The discussion of stereoselectivity, Felkin Anh, chelation, electron donating substituents on the alpha carbon next to the ketone is elegant.  You don’t have to memorize anything — just think.  However, all is so well explained, that it’s unlikely that there is further research to be done on the subject, except when you’re trying to make something new.  

p. 865 — Any ideas why the lowest energy conformation of the carbon next to a double bond has one of the atoms attached to this carbon in the plane of the double bond (e. g. eclipsing the double bond).  Ken Houk was impressive as an undergraduate, and was already solving problems in the (subsequently legendary) Woodward seminars.

p. 872 — The synthesis of methyl mycaminoside with 5 asymmetric centers in a 6 membered ring, and reminds me of Woodward’s synthesis of reserpine, which also has 5 asymmetric centers in a 6 membered ring.   Particularly nice the way the synthesis used many of the stereochemical principles seen earlier in the chapter. 

p. 875 — I don’t see how the stereochemistry of L-isoleucine is preserved when the NH2 group is diazotized and then replaced by OH.   Well, I didn’t see it at first reading, but a few paragraphs later it was explained.  Shows that I’m still conscious I guess. 

Away for a bit

Off to my wife’s 50th high school reunion (classmate Jim Morrison, older matriculee — Mama Cass).  Back in a bit with the answer why big Pharma is imploding.  It’s basically what Derek Lowe has been saying — we are screwing around with a system we don’t understand fully.  The latest example of previously unsuspected cellular control mechanisms involves microRNAs, junk DNA, pseudogenes, and the difference in size between the genomes of leprosy and TB.   That’s just for openers — so rest up, see a few old friends and relax, maybe look at the Molecular Biology Survival Guide for Chemists if the terms make you feel anxious.

Back in the Saddle Again

Followers of this blog probably wonder where all the chemistry went.  I was in the middle of Anslyn and Dougherty when my iMac G5 began crashing earlier  this summer. So I had to put things on hold — for just why see – https://luysii.wordpress.com/2011/07/19/posting-intermittency-hypercard-r-i-p/.

I’ve now been able to transfer the HyperCard Data to FileMaker Pro 11, a program actively supported by the company that makes it, and a large user community.  Learning to program it was one of the most frustrating intellectual experiences I’ve ever had.

Readers of blogs like this one likely are always trying to learn new things, and invariably run up against concepts hard to understand the first time around.  I’m still trying to see how the various definitions of tensors are really about the same thing.  Mathematicians describe them as being over modules rather than vector spaces.  Physicists use vector spaces over the real numbers.  Other definitions stress multilinearity.  The concept of phase transition and what a renormalization group really does to explain it are currently beyond me.  I don’t think that anything in chemistry is that subtle (assuming you don’t get into the quantum mechanics of it all).  In medicine, it’s acid base balance and electrolytes, everything else is pretty simple once you memorize 50,000 facts.

But there’s always a place you can go to find the answers to your questions.

Not so, with learning FileMaker Pro.  There are reams of documentation, all sorts of bells and whistles of the program.  The problem is finding answers to the simplest of questions.

Pick up a “FileMaker 9 Developers Reference” and you’ll find all sorts of mention of values returned by functions. They never define just what a value is. “Ditto for FileMaker Pro 11 The Missing Manual”, value isn’t in the index, even though functions about them are.  Modern languages are very strongly typed — variable names must be declared and the program told what type it is — which type of numeric, text, function etc. etc.  The first few scripts I saw in this and other books had variables defined by “Let variable = something”.  About 150+ pages into one of these books (and “FileMaker Pro 10″ by Cologon which I think is the best of the lot) do you learn that variables are brought into existence just by naming them.  Similarly, the way a given field in a table is addressed in a script was never stated explicitly in any of the books, just mentioned in passing in one of them.  Basically I had to read all 3 of these books sequentially to find what I wanted.  I still don’t have a list of key words in the language, nor do I know what characters can’t be used in an identifier.  Basically I picked it up the same way an infant learns language, — by observing usage.   It could have been much easier, if the stuff that “everybody knows” was made explicit at the start.   I’ve never been so frustrated trying to learn anything, and it’s not because the material is difficult.

Rant now over,  the next post will describe some of the incredibly complex and subtle ways that the product of a protein coding gene can have different outcomes depending . ..  I’ts of some philosophic interest because it shows how crucial (fairly simple) chemistry is to understanding what’s going on, and yet, on a higher level, inadequate or irrelevant.  Stay tuned (those of you who haven’t given up).  I can’t wait to get back to finishing Anslyn and Dougherty (and posting about it)

 

Posting Intermittency — HyperCard R.I.P.

The frequency of posts is about to diminish.  I’ve got to learn a new program, and its programming (scripting) language to shift my current database to it.  I started using HyperCard when it came out in the fall of 1987, using it for all the notes I took on my reading in various areas.  You can even draw chemical structures with it, but not easily.   It’s a marvelous program and I’d be using it still if Apple still supported it (something they’ve not done in a decade).  When I was in practice, I ran its business side using it.  It’s extremely easy to program, user friendly , enough so that I wrote my own billing software, saving a bundle.   When Apple moved to Intel processors, Hypercard didn’t move with it, and so I had to buy 2 old machines using the PowerPC and OS 9.  The first versions of OS X had a classic mode which still supported Hypercard on the PowerPC.  The newer versions of OS X will not.  Machines eventually fail and I’m not about to have all the work I’ve put in, fail with it.

The database  contains 14,093 cards in the Xref stack, which is basically text, 18,892 cards in the index stack, and 7658 in the Glossary stack.  The great thing about Hypercard is that it lets you link two cards in any stack together by buttons.  Why is this great?  Because science progresses by the unexpected.  No one would have thought that the gene for narcolepsy would be related to appetite, but it is.  All it takes is a button to link the two cards with information about either together.  So the index stack has 47,498 buttons, xref 34,282 and glossary 11572, bringing the total number of cards and buttons to a glorious 133,995.  The whole shebang takes up 72 megaBytes on Disk.

This sort of thing was foreseen years ago in a great book called “Silicon Snake Oil: Second Thoughts on the Information Highway” by Clifford Stoll.  His point, is that storing things digitally is a con, as programs and their formats are no longer supported.  It certainly happened to me, although it’s been a great 24 years.  He also wrote another very good book called the “Cuckoo’s Egg” about how, as a graduate student in Astrophysics, he came across a few accounting errors in the accounts he was called to manages — pennies only, as I remember. It led to the discovery of a ring stealing all sorts of money from accounts all over the world.  It’s well written and funny.

So I’ve decided to learn FileMaker Pro, which also has a scripting language and which appears powerful enough to do so.  I went to a training session today which introduced the basics, and was very pleased to see that the Broad Institute (of human genome project fame) and Tufts NeuroScience sent 3 people.  The program has been around a long time (in computer time, that is) and hopefully will continue.  I’ve found “FileMaker Pro 11, The Missing Manual”quite helpful, although I’ve only worked through 70 or so of its 800+ pages.

I’ve already figured out how to get the text content of the various fields stacks and the scripts of the buttons of my HyperCard stacks into a plain text file which I can simply schlep over to the newer Apples.    Now I have to learn the scripting language of FileMaker Pro to get this data into a Filemaker database (which won’t be hard to construct, since it will mimic the functionality of the old one).  If anyone out there knows of  a (free) good source explaining the FileMaker Pro scripting language, rather than just listing the commands and syntax, please  let me know.  While you can learn a new language from a dictionary, there are better ways to do it.  Today’s training session already set me back $300 (well worth it though !), and FileMaker Pro Advanced will be $500.

Ave Caesar ! Morituri te salutamus

This is what the gladiators said to Caesar before fighting to the death.  Now we have March madness.  These morbid thoughts are brought about about by thought of another Ivy League champ playing the scholars of Kentucky. Last year Cornell got creamed by them, and, according to my son who went there, one of the Freshman players from that Kentucky team is now doing quite well in the NBA, thank you.

Last Sunday’s New York Times magazine had an article worrying if big time college basketball was dying, because their best players left after a year to join the NBA.  Not to worry, their sports section that day covered the Ivy league playoff between Princeton and Harvard, calling it (accurately) an Ivy League Thriller.  I watched it, having been associated with both schools in the remote past. When the largest lead is under 10 and when it changes hands 3 times in the final sixty seconds, with the winning shot released with 200 milliSeconds to go, that’s a fair description.

The game was hard played, but without coaching histrionics, technical fouls, etc. etc.  No player will is likely to go to the NBA, but all are likely to graduate, and have a life thereafter.  As one of the Princeton players said “we love the game as much as anyone”. Basketball will survive the demise of big time college basketball, even if  the fans don’t.  It’s a great game.  Needless to say basketball has changed.  My father (Rutgers ’28) told me, that coaches would chew him out for shooting one handed.

Historical note:  the picture of the Princeton band in the Sunday Times have them looking just as dorky as when I was in it.  However, they do sound a lot better.  Don't snicker too much, one of our trumpet players later became president of the university of Chicago. 

One hopeful note for the Ivies.  The Princeton coach, Sydney Johnson, played on the Princeton team that defeated UCLA (the previous year’s champ), so you never know.

Posting delay

When you all get out into the world, you will find things to occupy your time which are far from pleasant.  I’ve received some strong criticism of what I’ve written so far, which deserves a response.  But life intrudes, so there will be a delay.  In the meantime read up on familial amyloidotic polyneuropathy, sickle cell disease, Motoo Kimura’s work on neutral mutation and have a look at http://luysii.wordpress.com/2010/05/23/how-fast-is-your-biological-clock-ticking-well-know-soon/

#1 (and worst) a young family member has dropped out of college this fall and is almost certain to be in the early stages of schizophrenia. While chemistry and pharmacology will give him a better life than a state hospital would have 50 years ago, it will not be a full life.  It’s essentially a death in the family (the parents are still in denial).  At least they don’t have to be told that it is their fault, as some psychiatrists were wont to do 50 years ago.

#2 (not as bad but still bad).  My brother’s wife’s brother passed away — a lifelong schizophrenic.  He dropped out of Penn at the same age and for the same reason (he couldn’t think despite high intelligence) as #1 about 40 years ago, so the family now has a replacement.

#3 We are presently fighting a zoning battle to keep a casino away from our door.  Compared to #1 and #2 this is trivial.  This may be why docs seem so unfeeling at times.  They have their nose rubbed in the really serious stuff every day. 

Where I’m coming from

Before plunging into some very long (and quite overdue ) responses to people good enough to comment on previous posts about whether chance alone is enough to explain our existence, it’s time for a few words why I’m so skeptical about the received wisdom, particularly in molecular biology.  Psychological background can never alter scientific facts, but it certainly alters  the way theories are viewed.

The commenters I’ll be addressing are quite sophisticated, so this and the next post will likely be tough going for those outside the field.  For some background see http://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/ and http://luysii.wordpress.com/2010/07/11/molecular-biology-survival-guide-for-chemists-ii-what-dna-is-transcribed-into/

I was in grad school studying organic chemistry ’60 – ’62, a time when the actual genetic code was being worked out (e.g. which triplet of nucleotides coded for which amino acid).  Given that background, it was fairly easy to keep up with molecular biology as it grew and flowered (also it gradually became more and more important for medicine).  

This means that I’ve seen statements given by the highest authorities turn out to be absolutely wrong.  Gunther Stent proclaimed in 1969 that the end of molecular biology had been reached.  No small fry, he later went on to become chair of the molecular biology department at Berkeley from ’80 – ’86 (he must have recanted).

Consider the statement that Chimps and Humans were so close genetically that they should be considered the same species.  Genes in this case being the 1.5 % of the genome coding for protein.  The rest being Junk DNA (and considered unimportant at the time the statement was made).   

Consider Paul Ehrlich’s Population Bomb which predicted we’d be starving in the dark 10 years ago, or the prognostications of the Club of Rome in 1972 “The Limits to Growth” which sold 30,000,000 copies and was taken very seriously.  

No one believes that our genome is junk any more, but the nomenclature lives on.  Look at Cell vol. 143 pp. 46 – 58 ’10 (1 October issue).  ”Long Noncoding RNAs with Enhancer-like Function in Human Cells”  Another term for them is lincRNAs (long INTERGENIC RNAs), the implication of intergenic being that they aren’t genes.  But of course they are.  A mere 3,000 of them were found looking at about 1/3 of the genome, implying that they are probably half as abundant as proteins.  Just because they don’t code for protein doesn’t mean they aren’t genes.  The paper shows that some of them modify protein expression (increasing it, unlike microRNAs of which we have at least 1,000, which usually decrease protein levels).  

For most of you, this is ancient history, but I’ve lived through it, which makes me skeptical about grand pronouncements such as global warming or the idea that the complexity of life (which grows more complex all the time as we discover new players like microRNAs, lincRNAs, etc. etc.) just arose by chance.  If it doesn’t make sense to me, I’m not going to buy it, no matter how eminent the authority. This is NOT the same thing as saying they’re wrong.

Among the things I don’t understand (1) why a protein should have one or a few shapes — clearly 20,000 of them do or we wouldn’t be here  (2) why the side chains of proteins don’t react with each other more often, a la Green Fluorescent Protein (3) how the incredible fidelity of DNA replication could have arisen — see http://luysii.wordpress.com/2010/05/23/how-fast-is-your-biological-clock-ticking-well-know-soon/ where the error rate between parent and child is 1/100,000,000 (in one family anyway) (4) how the elaborate dance of the topoisomerases with DNA could have arisen by random mutation.

Away for a bit

As my cousin’s husband once said, the problem with retirement is that you never get a day off.  I’ll be back in a week or so.  For a few laughs see http://pipeline.corante.com/archives/2010/09/17/spread_of_the_pun_virus.php
Stay well.