A friend of mine just returned from a conference in New York organised by Schrodinger, and I have to say that Schrodinger really seems to be poised to be the one-stop shop for all things computational.
They already have some great programs in their Maestro suite, including Glide for docking, which you find folks in industry using more and more these days. In their next revisions, they are going to introduce a program named PrimeX for doing crystallography, which will perform analysis similar to CNS, which will be groovy if it brings such analysis to the desktop. They are also going to introduce electron-density fitting for loop refinement in proteins. Right now, loop refinement of, say a 10 residue loop takes forever. But with PrimeX and friends, one can have constraints effected by electron density to restrict conformational searching, thus greatly speeding up the process.
Other products include the very impressive new Glide XP docking protocol. I have been glued to their site ever since they published their admirable paper in 2006. I have already written about the capabilities of GlideXP. This is really the best of computational chemistry applied to docking, where you find chemists trying to include as many experimental parameters as they can in a program. Schrodinger is definitely one company whose chemists have a firm and steady hand on experimental variables.
A very important development is going to be the interfacing of William Jorgensen's MCPRO, a program for doing free energy perturbation (FEP) calculations. FEP calculations are as close as you can come to accurately reproducing experimental binding free energies, one of the holy grails of computational methodology. While GlideXP astoundingly claims to also be able to do that, it would be super to have a GUI and easy operability for a good FEP program at your fingertips. Admittedly, FEP works only for ligand which differ little in their structure (eg. Me vs H). But that's also the phenomenon which we understand the least, how "similar" ligands can have great differences in binding affinity, something which FEP should help us understand.
Other improvements will include better parameters in standard docking, and a new force field, OPLS 2008, which will be "better than MMFF". Considering that the force behind this field is Tom Halgren, the same guy who meticulously crafted MMFF, I would be looking forward to it. There is also talk of a new MD program comparable to Gromacs, AMBER etc. which can do millisecond MD efficiently. That would probably complete the list of capabilities in one program that almost any computational chemist could want.
What I like best about Schrodinger is that it has people at its helm who are among the best that computational chemistry has to offer, most importantly Richard Friesner and Tom Halgren. Looking at their papers, it's clear that like ideal computational chemists, they thoroughly understand experimental data, and clearly know what the limitations of their programs are.
Decide how you want to die...
...by scurvy or DNA damage. Hopefully, none.
An interesting study has appeared in the British Journal of Nutrition (2007, 97, p.639), which seems to say what many of us may have suspected; that nature knows best. The study investigates the effect of Vitamin C as an antioxidant when taken alone in the form of pills, or as a component of oranges or orange juice.
The study made volunteers drink Vit C water, orange juice, and sugar water as a control. After the Vit C levels in all the volunteers' blood were equalised, samples were taken and were exposed to hydrogen peroxide, a known DNA damage agent. Surprisingly, the levels of DNA damage were much lower in the orange juice-fed volunteers than the Vit C water volunteers.
I have not had access to the full paper, but the authors conjecture that it may be the other substances in oranges which protect against DNA damage. As I see it, these other substances may be acting as "sacrificial" molecules, themselves getting oxidised and thereby protecting both DNA and Vit C.
Actually, these results should not be surprising. Nature has evolved intricate packages of chemicals that play roles in organisms. Oranges are not just containers for holding Vit C and other compounds, but intricate systems in which there is an essential synergistic interplay of all these substances as well as their container. Taking one out of context creates the same problems as when politicians take words out of contexts. As in many aspects of of nature, the whole is much more than the sum of the parts. In light of this, I sometimes wonder how we have so many effective drugs which are isolated from natural sources and used separately. But then, it's not perfect, is it? Think of how many side effects they have, and this may well be because you are not providing a holistic environment for them to act. Sometimes the leaf is really better than the pill. Validation for old Ayurveda and herbal medicine?
Next time, maybe we can think twice before we substitute a Vitamin tablet for its natural source.
An interesting study has appeared in the British Journal of Nutrition (2007, 97, p.639), which seems to say what many of us may have suspected; that nature knows best. The study investigates the effect of Vitamin C as an antioxidant when taken alone in the form of pills, or as a component of oranges or orange juice.
The study made volunteers drink Vit C water, orange juice, and sugar water as a control. After the Vit C levels in all the volunteers' blood were equalised, samples were taken and were exposed to hydrogen peroxide, a known DNA damage agent. Surprisingly, the levels of DNA damage were much lower in the orange juice-fed volunteers than the Vit C water volunteers.
I have not had access to the full paper, but the authors conjecture that it may be the other substances in oranges which protect against DNA damage. As I see it, these other substances may be acting as "sacrificial" molecules, themselves getting oxidised and thereby protecting both DNA and Vit C.
Actually, these results should not be surprising. Nature has evolved intricate packages of chemicals that play roles in organisms. Oranges are not just containers for holding Vit C and other compounds, but intricate systems in which there is an essential synergistic interplay of all these substances as well as their container. Taking one out of context creates the same problems as when politicians take words out of contexts. As in many aspects of of nature, the whole is much more than the sum of the parts. In light of this, I sometimes wonder how we have so many effective drugs which are isolated from natural sources and used separately. But then, it's not perfect, is it? Think of how many side effects they have, and this may well be because you are not providing a holistic environment for them to act. Sometimes the leaf is really better than the pill. Validation for old Ayurveda and herbal medicine?
Next time, maybe we can think twice before we substitute a Vitamin tablet for its natural source.
Analogies between analogies: The character of Stan Ulam
Derek's post about metaphors and analogies reminded me of a quote by a remarkable mathematician whose name is known only to aficionados now, but who stands in the front rank of brilliant mathematicians and physicists of the twentieth century- Stanislaw Ulam. Here's a quote from him about analogies:
Ulam was born in Poland and grew up in a romantic time in the 20s and 30s, when great discoveries in mathematics and physics were being made in small, enchanting roadside cafes by small groups of people working intensely together. One of those, the Scottish Cafe in Lwow, Poland, was a focal point for meeting of great minds, the best pure mathematicians in Europe. Equations used to be scribbled on tables there, and the waiters were told never to erase them. Marathon sessions used to be common, fueled by black coffee, and interrupted only by occasional meals and trips to the bathroom; one non-stop session lasted 17 hours. The mathematician Rota said this about Ulam's fascinating mind:
After coming to the US, Ulam was secretly invited to join the Manhattan Project in Los Alamos, where he was known to be a problem solver and jovial team worker. In Los Alamos, he tried to recreate the idyllic atmosphere of his young years in Europe by installing a coffee machine outside his office where scientists could talk shop. You can get to see Ulam in The Day after Trinity. Here is a photo of three prodigies from those days, (From L to R) Ulam, Richard Feynman, and John Von Neumann
While at Los Alamos, Ulam made what was probably the most important contribution of his career- the Monte Carlo method, a way of calculating the result of complex processes through random numbers. This method is now so important and deep-rooted in physics, chemistry, and engineering, that many students have forgotten that somebody invented it. The method is now implemented as a black box in many computer programs, such as those which I use for calculating the structure of organic molecules, and so people tend to sometimes use it without knowing that they are using it.
In 1946, Ulam suffered an attack of encephalitis; he could not remember events after the attack, and after the operation, federal agents asked him questions to make sure that he may not have given away atomic secrets during his loss of recollection. After the operation, Ulam seemed to some to become even more brilliant than he had been before.
However, Ulam probably became best-known to a greater audience through his participation in the development of the hydrogen bomb. After the war, he and fellow scientist Cornelius Everett embarked on a series of tedious calculations to prove that the then accepted and widely touted design of the hydrogen bomb would not work. This was a significant result, as President Harry Truman had been earlier prodded to announce a crash effort to develop the bomb based on this design. WIthin a short time however, Ulam came to the essential breakthrough that encouraged the infamous Edward Teller to develop the most widely used design of the h-bomb. The breakthrough involved separating the fission and fusion parts of the weapons, and using compression from the fission bomb to activate the fusion bomb. After this design was invented, everybody assumed that the Soviets were doing it too, and the program was purused with vigour. Every country afterwards that developed thermonuclear weapons has used this so-called "Teller-Ulam" design or a variant of it.
The imperious Teller essentially took much of the credit for the invention, and later tried to expunge Ulam's name from that part of history. Hans Bethe liked to joke that Ulam was really the "father of the h-bomb" while Teller was the mother since he carried the baby for so long. Ulam for his own part, an unassuming and docile man, stayed away from these disputes, when he rightly could have done more for asserting his claim to fame. Ulam and Teller parted ways after the discovery, Ulam returning to his world of pure science, and Teller becoming increasingly belligerent and disliked by his fellow scientists, and pushing for new and "better" nuclear weapons, thus becoming what Richard Rhodes calls the "Richard Nixon of American science". Till the end of his life in 2004 at the age of 95, he gave hawkish and wrong advice to Presidents (famously about "Star Wars" to Ronald Reagan) and believed that he was doing the right thing in advancing peace by building more hydrogen bombs.
During his professional career, Ulam spent time at the Universities of Wisconsin, UCLA, and Boulder. His wife, Francoise, was always a loving support as well as an admirer of him. She remembers one defining moment from their lives, when she found her husband staring out the window after he had had the idea for a successful hydrogen bomb. "I have just discovered the idea that will change history", he presciently said.
Ulam died in 1984. An astonishingly versatile scientist, he had been equally at home with the most abstruse reaches of set theory and with the details of thermonuclear fusion. His memoirs, Adventures of a Mathematician, paints a fascinating and delightful portrait of the golden age of physics and mathematics, as well as the dawn of the nuclear age. In this book, we get to hear anecdotes about famous mathematicians and physicists, many of whom were good friends of Ulam.
Ulam once said:
"Great scientists see analogies between theorems or theories. The very best ones see analogies between analogies"Indeed. And Stan Ulam could very well put himself into the second category, although his modest nature would have not made him do so.
Ulam was born in Poland and grew up in a romantic time in the 20s and 30s, when great discoveries in mathematics and physics were being made in small, enchanting roadside cafes by small groups of people working intensely together. One of those, the Scottish Cafe in Lwow, Poland, was a focal point for meeting of great minds, the best pure mathematicians in Europe. Equations used to be scribbled on tables there, and the waiters were told never to erase them. Marathon sessions used to be common, fueled by black coffee, and interrupted only by occasional meals and trips to the bathroom; one non-stop session lasted 17 hours. The mathematician Rota said this about Ulam's fascinating mind:
"Ulam's mind is a repository of thousands of stories, tales, jokes, epigrams, remarks, puzzles, tounge-twisters, footnotes, conclusions, slogans, formulas, diagrams, quotations, limericks, summaries, quips, epitaphs, and headlines. In the course of a normal conversation he simply pulls out of his mind the fifty-odd relevant items, and presents them in linear succession. A second-order memory prevents him from repeating himself too often before the same public."Ulam was invited to visit the US as a lecturer several times during the 1930s by his fellow famous emigre from Europe, and admittedly the smartest man of his generation; John Von Neumann. Within a short time, the romantic days were at a tragic end. Ulam held out in Poland much longer than many other brilliant European scientists and mathematicians, and in 1939, on the eve of World War 2, escaped to America with his brother Adam. The rest of the Ulam family perished in the Holocaust.
After coming to the US, Ulam was secretly invited to join the Manhattan Project in Los Alamos, where he was known to be a problem solver and jovial team worker. In Los Alamos, he tried to recreate the idyllic atmosphere of his young years in Europe by installing a coffee machine outside his office where scientists could talk shop. You can get to see Ulam in The Day after Trinity. Here is a photo of three prodigies from those days, (From L to R) Ulam, Richard Feynman, and John Von Neumann
While at Los Alamos, Ulam made what was probably the most important contribution of his career- the Monte Carlo method, a way of calculating the result of complex processes through random numbers. This method is now so important and deep-rooted in physics, chemistry, and engineering, that many students have forgotten that somebody invented it. The method is now implemented as a black box in many computer programs, such as those which I use for calculating the structure of organic molecules, and so people tend to sometimes use it without knowing that they are using it.
In 1946, Ulam suffered an attack of encephalitis; he could not remember events after the attack, and after the operation, federal agents asked him questions to make sure that he may not have given away atomic secrets during his loss of recollection. After the operation, Ulam seemed to some to become even more brilliant than he had been before.
However, Ulam probably became best-known to a greater audience through his participation in the development of the hydrogen bomb. After the war, he and fellow scientist Cornelius Everett embarked on a series of tedious calculations to prove that the then accepted and widely touted design of the hydrogen bomb would not work. This was a significant result, as President Harry Truman had been earlier prodded to announce a crash effort to develop the bomb based on this design. WIthin a short time however, Ulam came to the essential breakthrough that encouraged the infamous Edward Teller to develop the most widely used design of the h-bomb. The breakthrough involved separating the fission and fusion parts of the weapons, and using compression from the fission bomb to activate the fusion bomb. After this design was invented, everybody assumed that the Soviets were doing it too, and the program was purused with vigour. Every country afterwards that developed thermonuclear weapons has used this so-called "Teller-Ulam" design or a variant of it.
The imperious Teller essentially took much of the credit for the invention, and later tried to expunge Ulam's name from that part of history. Hans Bethe liked to joke that Ulam was really the "father of the h-bomb" while Teller was the mother since he carried the baby for so long. Ulam for his own part, an unassuming and docile man, stayed away from these disputes, when he rightly could have done more for asserting his claim to fame. Ulam and Teller parted ways after the discovery, Ulam returning to his world of pure science, and Teller becoming increasingly belligerent and disliked by his fellow scientists, and pushing for new and "better" nuclear weapons, thus becoming what Richard Rhodes calls the "Richard Nixon of American science". Till the end of his life in 2004 at the age of 95, he gave hawkish and wrong advice to Presidents (famously about "Star Wars" to Ronald Reagan) and believed that he was doing the right thing in advancing peace by building more hydrogen bombs.
During his professional career, Ulam spent time at the Universities of Wisconsin, UCLA, and Boulder. His wife, Francoise, was always a loving support as well as an admirer of him. She remembers one defining moment from their lives, when she found her husband staring out the window after he had had the idea for a successful hydrogen bomb. "I have just discovered the idea that will change history", he presciently said.
Ulam died in 1984. An astonishingly versatile scientist, he had been equally at home with the most abstruse reaches of set theory and with the details of thermonuclear fusion. His memoirs, Adventures of a Mathematician, paints a fascinating and delightful portrait of the golden age of physics and mathematics, as well as the dawn of the nuclear age. In this book, we get to hear anecdotes about famous mathematicians and physicists, many of whom were good friends of Ulam.
Ulam once said:
"It is still an unending source of surprise for me how a few scribbles on a blackboard or on a piece of paper can change the course of human affairs."Ulam was certainly one of the select few who scribbled.
How not to design a fly killer
Raid "Earth Options" Flying Insect Killer, the supposedly environment-friendly fly spray, is admittedly the worst designed fly killer I have come across until now. I doubt if even the manufacturers themselves knew what composition and materials they put in, and even if they did they don't seem to have actually tested it. For one thing, I don't know if it's because it's supposed to be benign, but its sheer potency is just lousy. You have to spray it directly on the fly, and more often than not the little critter ends up flying around before it suffers a direct hit, so that you mostly end up spraying everywhere else except on it. Even when it is hit, it usually struts around for a few random centimeters before finally falling dead, thus parading microscopic globs of the chemical all over the place. And in some death defying instances, I have even seen flies getting up, dusting themselves off as if nothing happened, and resuming their flying antics.
But the most annoying thing about Raid Earth Options is their aerosol composition, which is extremely poorly designed. The stuff does not perform even its basic function, to get finely aerosolized. I don't what exactly was circulating in the bloodstream of the chemist/engineer who designed it. When you spray the stuff, the particle size it produces is quite large, and so the droplets quickly drop like a stone on whatever surface is below. Because of this problem, not only does it not hang around long enough in the fly's flying space, but one can never use it on tubelights, where flies usually sit, because usually the tubelights are right above your desk and everything on it. The first few times I used it, I had to discard some papers on my desk, clean up the whole surface, and yes, throw away a box of cookies that was actually sitting quite far from where I sprayed the fly killer. I don't think environment-friendly means you can use it as hot sauce for your fried rice.
This problem dictates that to avoid a thin and pretty long-lasting coating on everything in my room, I always lure the fly into a bathroom by turning off all lights except the one there, and then turn the whole bathroom atmosphere into a Raid fest. And don't even think of using it anywhere in your kitchen. Plus, the smell is not exactly enticing, for humans and flies. Dismal. Others seem to agree.
S.C. Johnson and Co., for all those heartwarming commercials that portray three generations of dedicated product manufacturers, shame on you for selling us Raid Earth Options. I do like your Ziploc and Saran Wrap.
Trans-biotin?
Questiion for all the synthetics out there: Does anyone know how common, if at all, is trans-biotin, where the two five-membered rings are fused in a trans manner? If not, how easy/hard is it to make it?
New tagline for SBDD
I have come up with a new tagline for structure based drug design:
For instance, you may think, "Hey, that group seems to hydrogen bond with an NH hydrogen; let me make it more electronegative by putting a nitro group somewhere close to it. Oops! That changed the binging mode completely. Tough luck".
Or "Hmm...it seems that this part of the molecule that forms all these hydrogen bonds is similar to that other molecule in that other protein-ligand complex which shows swashbuckling picomolar activity. Why don't I modify this part of the molecule to resemble the other molecule then?...Oops! Changed the entire binding mode again."
And did I mention...the tagline actually should be "Semi-rational or irrational in foresight, almost always irrational and sometimes rational in hindsight"
And all this is only at the molecular level; I don't even have to get started on how small changes can play havoc with things like solubility, pharmakokinetics and bioavailability, and of course, the notorious tox. Chemists are long familiar with what the addition of a single methyl group can do to binding and activity. At the same time, it's curious how there in fact are so many inhibitors binding to a certain class of proteins that may differ radically in other parts, yet have a highly conserved set of atoms which consistently bind to the same part of the protein. Almost miraculously, all those changes in the other parts don't seem to affect the way those few atoms bind to the protein; the best example that comes to my mind is that almost ubiquitous set of 'hinge binding' atoms in protein kinase inhibitors that mimics the ATP motif. Of course, this makes them wildly non-selective because almost no kinase is 'unhinged', but often puts you at a good starting point in terms of potency.
The fact, we still have miles to go in understanding the subtleties of protein-ligand interaction. But we have also made a mighty fine start in understanding, among other things, subtle differences in Van der Waals interactions, desolvation and entropic penalties, bioisosterism (or the lack thereof), and most recently, the role of water in ligand binding.
It's a good day to be alive sir.
"Semi-rational in foresight, rational in hindsight"And in fact I think that could apply to many aspects of designing drugs.
For instance, you may think, "Hey, that group seems to hydrogen bond with an NH hydrogen; let me make it more electronegative by putting a nitro group somewhere close to it. Oops! That changed the binging mode completely. Tough luck".
Or "Hmm...it seems that this part of the molecule that forms all these hydrogen bonds is similar to that other molecule in that other protein-ligand complex which shows swashbuckling picomolar activity. Why don't I modify this part of the molecule to resemble the other molecule then?...Oops! Changed the entire binding mode again."
And did I mention...the tagline actually should be "Semi-rational or irrational in foresight, almost always irrational and sometimes rational in hindsight"
And all this is only at the molecular level; I don't even have to get started on how small changes can play havoc with things like solubility, pharmakokinetics and bioavailability, and of course, the notorious tox. Chemists are long familiar with what the addition of a single methyl group can do to binding and activity. At the same time, it's curious how there in fact are so many inhibitors binding to a certain class of proteins that may differ radically in other parts, yet have a highly conserved set of atoms which consistently bind to the same part of the protein. Almost miraculously, all those changes in the other parts don't seem to affect the way those few atoms bind to the protein; the best example that comes to my mind is that almost ubiquitous set of 'hinge binding' atoms in protein kinase inhibitors that mimics the ATP motif. Of course, this makes them wildly non-selective because almost no kinase is 'unhinged', but often puts you at a good starting point in terms of potency.
The fact, we still have miles to go in understanding the subtleties of protein-ligand interaction. But we have also made a mighty fine start in understanding, among other things, subtle differences in Van der Waals interactions, desolvation and entropic penalties, bioisosterism (or the lack thereof), and most recently, the role of water in ligand binding.
It's a good day to be alive sir.
R.I.P Frank
Frank Westheimer, rest in peace. I will never forget your Why Nature Chose Phosphates, which was brilliant. Rest assured, you will be more than a footnote to a footnote in the history of chemistry.
Questions for the kinase biologists
I am working on a kinase inhibitor design project and I realised that there are some key questions that we need to get answered from the biologists before we can rationalize the selectivity of various kinase inhibitors for a given binding site. I also realised that these questions need to be answered for many other kinds of protein-inhibitor interactions.
1. Whenever we get different IC50 data for two inhibitors, we immediately try to look at binding interactions that may be different for the two moelcules to rationalize this observation. But as I have alluded before, it's not the IC50 but the Ki that's really to do with different binding interactions. The Ki and IC50 are related by an equation that includes both the Km value of ATP and the concentration of ATP in the two experiments, or in general, these two parameters for the natural binding substrate for the protein. Only if these two are the same for both inhibitor experiments is the IC50=Ki. So make sure you confirm this. Otherwise, extrapolate and calculate the new IC50s based on identical values for these parameters. Then rationalize the IC50s based on binding interactions.
2. For many kinases, three events are absolutely essential for activation:
a. Phosphorylation of one Ser, Thr or Tyr residue,
b. Binding of ATP (duh), and
c. Dephosphorylation of another Ser, Thr or Tyr residue.
Think of it like a logic gate. IF the answers to all a. b. and c. are YES, THEN the kinase will be activated and proceed to perform its function. (I got this from Alberts et al.'s Molecular Biology of the Cell)
In the assays that are run, it is important to know (and not very easy to always determine as I have been told) whether the necessary residue is phosphorylated or not. For one thing, inclusion of this knowledge in your docking and modeling can naturally make a big difference. And secondly, depending on the state of phosphorylation, you can think of different modes of inhibition for your inhibitor (eg. ATP blocking + substrate blocking).
As usual, it's important to know what the biologists are doing. They don't know the nuances of modeling/crystallography and you don't know the nuances of their assays. But it's important for both camps to think of questions which the other camp should answer that will affect their own work.
1. Whenever we get different IC50 data for two inhibitors, we immediately try to look at binding interactions that may be different for the two moelcules to rationalize this observation. But as I have alluded before, it's not the IC50 but the Ki that's really to do with different binding interactions. The Ki and IC50 are related by an equation that includes both the Km value of ATP and the concentration of ATP in the two experiments, or in general, these two parameters for the natural binding substrate for the protein. Only if these two are the same for both inhibitor experiments is the IC50=Ki. So make sure you confirm this. Otherwise, extrapolate and calculate the new IC50s based on identical values for these parameters. Then rationalize the IC50s based on binding interactions.
2. For many kinases, three events are absolutely essential for activation:
a. Phosphorylation of one Ser, Thr or Tyr residue,
b. Binding of ATP (duh), and
c. Dephosphorylation of another Ser, Thr or Tyr residue.
Think of it like a logic gate. IF the answers to all a. b. and c. are YES, THEN the kinase will be activated and proceed to perform its function. (I got this from Alberts et al.'s Molecular Biology of the Cell)
In the assays that are run, it is important to know (and not very easy to always determine as I have been told) whether the necessary residue is phosphorylated or not. For one thing, inclusion of this knowledge in your docking and modeling can naturally make a big difference. And secondly, depending on the state of phosphorylation, you can think of different modes of inhibition for your inhibitor (eg. ATP blocking + substrate blocking).
As usual, it's important to know what the biologists are doing. They don't know the nuances of modeling/crystallography and you don't know the nuances of their assays. But it's important for both camps to think of questions which the other camp should answer that will affect their own work.
Some clerihews
Plug in your own into the comments, and I will gladly update the post!
Albert Einstein
Led by a godly sign
Engaged in spacetime-talk
Forgot to wear a sock
Robert Burns Woodward
Once looked skyward
By cogitation alone
Made strychnine from stone
Julius Robert Oppenheimer
Bought a millisecond timer
Before the timer struck one
Had read Tolstoy "just for fun"
Marie Curie
Exalted was she
Glee she was showing
When the beaker started glowing
Ernest Rutherford
Was made a Lord
By throwing many a dart
Straight into the atom's heart
Richard Philips Feynman
Much fun for the layman
When safes he was poking
Surely he was joking
Finally, an already known classic one (from the Oxford Dictionary):
Sir James Dewar
Is better than you are.
None of you asses
Can liquefy gasses!
Update:
Some choice ones from Peter Ellis,
Alfred Nobel
Did very well
By blowing up things of all sizes
Now his ghost atones for it with prizes
Watson and Crick
Make me feel sick
By uncovering the heart of everything
Using little toy balls and bits of string.
...and A Synthetic Environment.
Marie Curie,
Not hard to see,
Was glowing with pride,
And glowed in the night.
Herr Wöhler, Friedrich
He told his friend Liebig:
'Not now, sorry. See ya!
I’m pissing urea.’
Antoine-Laurent de Lavoisier,
Said : ‘Phlogiston theory is not okay,
This phlogiston theory is driving me mad,
I have to disprove it or I’ll lose my head.’
Robert H. Grubbs,
he visited pubs.
One pub let a bell ring,
That ring meant 'we're closing!'.
Albert Einstein
Led by a godly sign
Engaged in spacetime-talk
Forgot to wear a sock
Robert Burns Woodward
Once looked skyward
By cogitation alone
Made strychnine from stone
Julius Robert Oppenheimer
Bought a millisecond timer
Before the timer struck one
Had read Tolstoy "just for fun"
Marie Curie
Exalted was she
Glee she was showing
When the beaker started glowing
Ernest Rutherford
Was made a Lord
By throwing many a dart
Straight into the atom's heart
Richard Philips Feynman
Much fun for the layman
When safes he was poking
Surely he was joking
Finally, an already known classic one (from the Oxford Dictionary):
Sir James Dewar
Is better than you are.
None of you asses
Can liquefy gasses!
Update:
Some choice ones from Peter Ellis,
Alfred Nobel
Did very well
By blowing up things of all sizes
Now his ghost atones for it with prizes
Watson and Crick
Make me feel sick
By uncovering the heart of everything
Using little toy balls and bits of string.
...and A Synthetic Environment.
Marie Curie,
Not hard to see,
Was glowing with pride,
And glowed in the night.
Herr Wöhler, Friedrich
He told his friend Liebig:
'Not now, sorry. See ya!
I’m pissing urea.’
Antoine-Laurent de Lavoisier,
Said : ‘Phlogiston theory is not okay,
This phlogiston theory is driving me mad,
I have to disprove it or I’ll lose my head.’
Robert H. Grubbs,
he visited pubs.
One pub let a bell ring,
That ring meant 'we're closing!'.
The first miracle drug
Some idiot on a bicycle slammed into me yesterday. Fortunately I did not break anything, but the bruises are giving me an ucomfortable time since then. After rinsing both knees with chlorhexidine and iodine, I was not concerned; if there was an infection, antibiotics would take care of it.
But it wouldn't have been that way seventy years ago, when the most you could do to prevent a wound from getting infected...was wait, and perhaps apply some crude remedies. That was how it had been for two hundred years. For all the progress we had made, bad bugs still mostly got the better of us. It is appalling that about fifty percent of deaths in WW1 were from infections that riddled shrapnel wounds, and not from explosives or gunfire themselves. Once infection set in and gas gangrene made its hideous appearance, all one could do was wait, and maybe hope that the suffering would end soon...until sulfa drugs appeared on the scene.
That era of sulfa drugs, and not the one of penicillin, was the first heroic age of antibiotics. Most of us, if asked to name the first wonder-drug antibiotic, would name penicillin. But long before penicillin, sulfa saved thousands of lives. Without sulfa around, Hoover's son died. With sulfa, FDR's son, and Winston Churchill, survived. Thomas Hager has done an excellent job in bringing this forgotten but extremely important story to life in "The Demon Under the Microscope". The former biographer of Linus Pauling has shown us how different it was to suddenly have a drug that cured infections that previously would have almost certainly killed you. The time until the 1930s was a scary time, with every kind of Strep and Staph waiting to kill you after entering your body through the slightest cut, and diseases whose names we don't even remember now were rampant and much feared. It was sulfa that first declared war on and largely eradicated all these infections.
At the center of the sulfa story is the remarkable doctor and biochemist Gerhard Domagk. Domagk was an officer in WW1 and saw thousands needlessly die around him in agony, all because nobody could prevent the infection that set in after they were hit. After the war, Domagk went through a succession of jobs and finally ended up at Bayer, where he had a trailblazing career in the discovery of new cures for old infections. Building upon Paul Ehrlich's convictions about azo dyes as bacteriocidal agents, he and his colleagues tested hundreds of analogs, until he hit on the right one. This was the beginning of SAR as we know it today. And here, we can see the chemist's tragedy. Domagk tested the compounds, but it were two chemists who actually made them. Yet, they were excluded from the prize that Domagk would gather. This was not his fault, but really the workings of the Swedish committee, which did not behave this way for the first and last time. Patriotic and yet conscientious, Domagk stayed put after Hitler came to power, losing himself in his work to distract himself from the injustice that was taking place around him. In 1939, he was awarded the Nobel prize, but the Nazis did not allow him to accept it. Bayer itself became connected with the notorious IG Farben, which designed hydrogen cyanide vials (Zyklon B) for the gas chambers.
There is much in the book that is eye-opening, and sulfa is only one chapter in a book that also deals with medical history and the social history of science. There were several things I was unaware of; one revelation was that the modern American university model is based on the German model. The Germans were the world leaders in both industry and academia, and the modern and highly successful trend of close collaboration between industry and academia was already widespread in Germany. For all their philosophical bent, the Germans never saw any contradiction between pure and applied research, and the university-industry collaboration and connection led to very fruitful research in engineering and medicine. The modern patent regime too was pioneered by German industry.
The most important fact which I was not aware of was the pivotal albeit unfortunate role that sulfa played in revitalizing the FDA and granting it powers to implement laws that made it mandatory for manufacturers to display warnings and ingredients labels on their products. Before that, almost anyone could set up shop and sell metals, elixirs, and liquids that promised cures for everything from syphilis to baldness, a practice that went back two hundred years. But in the 1930s, through a series of unfortunate events, a concoction of sulfa in, of all the things, ethylene glycol, was sold extensively in many states. Today, we would be horrified at such large-scale use of an industrial solvent for mixing a drug. But at the time, there were almost no laws that required manufacturers to list such petty things as solvents on their bottles. The FDA was a skimpy and ineffectual agency at the time, with a few dozen agents scuttling around to mainly keep a check on excessive profit making. After the sulfa-ethylene glycol concoction was sold, a wave of death began that did not stop until several hundred people died, and public outrage changed the face of the FDA- and the way in which drugs are developed, manufactured and sold in the US- forever. After the tragedy, the FDA acquired new powers that it could have only dreamt of before. Of course, it took the thalidomide tragedy to have the kind of strict FDA regime that we have today, but the sulfa tragedy started it all, and made drugs substantially safer for the public.
An amusing and ironic chemical fact also accompanies the discovery of sulfa. Even though it were the Germans who pioneered its development, it was a French group that discovered the most important fact about the drug; that it was not the azo linkage, but the aryl sulfonamide group that was key to the action of the drug. Once they discovered this fact, all bets were off for the Germans, because the potent part of sulfa turned out to be benzene sulfonamide, a bulk chemical that could not be patented! Even if the Germans tried to quickly get past this handicap by synthesizing new derivatives at a terrific pace to outnumber their French colleagues, the cat was out of the bag, and they could never top their initial success.
Gradually, sulfa made it everywhere, and into the United States through the perspicacity and interest of two Johns Hopkins researchers. It began to be marketed in every form and colour and flavour, as every derivative and analog. In the 1930s, it became the drug of choice for treating every imaginable kind of Strep or Staph infection, most of which it effectively tackled. Cure by sulfa was touted as a miracle cure, with its relentless and wondrous effect on cases that only ten years ago would have been totally hopeless. But as a drug, sulfa had already fallen behind. Penicillin had arived on the scene. In due course, resistance would develop to both drugs, albeit relatively gradually to sulfa.
Domagk spent the last days of his life in gloomy peace, distraught by his country's destruction, and somewhat validated by the thousands of lives he had saved. Sulfa is still used for topical purposes.
We now know that sulfa competes with PABA for the synthesis of dihydrofolate. Sulfa and further related research led to, among other things, Methotrexate, a widely used current drug in cancer therapy. But in the end, what befell sulfa has befallen other antibiotics. The bugs have become resistant. When sulfa and penicillin were discovered, they were regarded as miracles. Perhaps we need another miracle for bad bugs today, and the age of fervent antibiotic research might be coming back to haunt us. But it should not be forgotten that sulfa was the first miracle drug, before penicillin.
Smells from the sea
One of the most fascinating things about perfumery is the source of its raw materials. Where the medicinal chemist can boast his sponges and tropical fungi, the fragrance chemist can boast some equally or more exotic sources for his materials. These constituents, in natural or synthetic form (usually synthetic; the natural ones are horrendously expensive) constitute the basis of those myriad notes that we smell, every time we use a shampoo or a soap, clean dishes with a detergent, or open a perfume bottle. Consider just two of them:
1. Ambergris:
Formed in the gut of the sperm whale. The whale’s gut contains a complex mixture of mucus, enzymes, and other secretions, which act on the food that it eats. After months of smoldering in the gut, it is finally burped out in the form of a huge blob, white in color, on to the surface of the ocean. But the story is not over yet. This blob floats on the surface of the ocean for months, sometimes years. The action of sunlight, oxygen, and seawater catalyzes a unique and complicated mixture of chemical reactions in it, causing it to become creamish-brown. The result is Ambergris, born of the sea, and washed up on the beach just like Amber (hence the name). The material is as valuable as it looks non-descript.
Ambergris is one of the world’s most prized perfumery materials. It is also one of the oldest perfumery materials documented, and records date back to the Egyptian era.
Natural Ambergris is fantastically expensive, priced in the international market at a cool 45,000 dollars or so per kilogram, many times its equivalent weight in gold. In the US, its possession is illegal, due to the ban on sperm whale hunting. However, I was very fortunate that my uncle, who works with a top perfumery company, had a tiny sample for me to smell. He had found it washed up on some beach once, and he had managed to get it to his lab and extract the invaluable material from it. The smell of ambergris is very rich and complicated, a mixture of many ‘notes’, as they are called by perfumers. ‘Animalic’ is the description of one of the main notes in the substance. These days, there have been many synthetic substitutes for ambergris, and these are used worldwide in a variety of perfumes and other products.
2. Oudh:
This mystical substance is found in a very few places in the world, India and Cambodia being two of them. In fact India is one of the main exporters of this substance to the West.
Like Ambergris, I found the origin of Oudh very fascinating.
There is a certain species of tree, mainly found in the Indian northeast and other parts of Southeast Asia. The tops of these trees get afflicted by a specific variety of fungus. The fungus attacks the wood, completely changing the color from an austere white to a decomposed, charred black. However, it is precisely this fungus-eaten wood that is the source of this priceless material. Again, I was fortunate to have smelt a sample. Like ambergris, oudh also has a complicated smell, with a distinct animalic note. It is also very expensive, costing anywhere from 25-50,000 dollars a kilogram, depending on its quality and source. Lower grades are naturally cheaper but also odor-contaminated. I have smelt all three of kinds of Oudh; Indian, Cambodian, and Vietnamese. The common animalic note is quite distinct in all of them. Each one of the varieties also smells a little of something that has been left out in the open for too long; unlike most of us, the French have long since learnt the value of such a character in perfumery.
1. Ambergris:
Formed in the gut of the sperm whale. The whale’s gut contains a complex mixture of mucus, enzymes, and other secretions, which act on the food that it eats. After months of smoldering in the gut, it is finally burped out in the form of a huge blob, white in color, on to the surface of the ocean. But the story is not over yet. This blob floats on the surface of the ocean for months, sometimes years. The action of sunlight, oxygen, and seawater catalyzes a unique and complicated mixture of chemical reactions in it, causing it to become creamish-brown. The result is Ambergris, born of the sea, and washed up on the beach just like Amber (hence the name). The material is as valuable as it looks non-descript.
Ambergris is one of the world’s most prized perfumery materials. It is also one of the oldest perfumery materials documented, and records date back to the Egyptian era.
Natural Ambergris is fantastically expensive, priced in the international market at a cool 45,000 dollars or so per kilogram, many times its equivalent weight in gold. In the US, its possession is illegal, due to the ban on sperm whale hunting. However, I was very fortunate that my uncle, who works with a top perfumery company, had a tiny sample for me to smell. He had found it washed up on some beach once, and he had managed to get it to his lab and extract the invaluable material from it. The smell of ambergris is very rich and complicated, a mixture of many ‘notes’, as they are called by perfumers. ‘Animalic’ is the description of one of the main notes in the substance. These days, there have been many synthetic substitutes for ambergris, and these are used worldwide in a variety of perfumes and other products.
2. Oudh:
This mystical substance is found in a very few places in the world, India and Cambodia being two of them. In fact India is one of the main exporters of this substance to the West.
Like Ambergris, I found the origin of Oudh very fascinating.
There is a certain species of tree, mainly found in the Indian northeast and other parts of Southeast Asia. The tops of these trees get afflicted by a specific variety of fungus. The fungus attacks the wood, completely changing the color from an austere white to a decomposed, charred black. However, it is precisely this fungus-eaten wood that is the source of this priceless material. Again, I was fortunate to have smelt a sample. Like ambergris, oudh also has a complicated smell, with a distinct animalic note. It is also very expensive, costing anywhere from 25-50,000 dollars a kilogram, depending on its quality and source. Lower grades are naturally cheaper but also odor-contaminated. I have smelt all three of kinds of Oudh; Indian, Cambodian, and Vietnamese. The common animalic note is quite distinct in all of them. Each one of the varieties also smells a little of something that has been left out in the open for too long; unlike most of us, the French have long since learnt the value of such a character in perfumery.
The Emperor of Scent
(Above: The book and its dilettante subject, perfumer Luca Turin)
Milo's post on fragrances reminded me of the seminar on a new theory of smell that I had given a few years ago, which initiated my interest in perfumery. The real impetus was a book named "The Emperor of Scent", about a maverick scientist named Luca Turin, who developed a new theory of smell based on vibrations of molecules instead of their shape, the traditional approach which does a pretty poor job at explaining SOR (Structure Odor Relationships).
Over the course of my seminar, I had an opportunity to communicate both with Luca Turin and Chandler Burr, the book's author. I remain interested in the area, and would sometime like to think of serious computational approaches that one could undertake to understand SOR.
I thought I would post my review of the book. For an introduction to the fascinating world of perfumery and smell alone, it's a fascinating read.
"Start with the deepest mystery of smell" says author Chandler Burr in the opening stanza. "No one knows how we do it. Despite everything, despite the billions the secretive giant corporations of smell have riding on it and the powerful computers they throw at it, despite the most powerful sorcery of their legions of chemists and the years of toiling in the labs and all the famous neurowizardry aimed at mastering it, the exact way we smell things–anything, crushed raspberry and mint, the subway at West Fourteenth and Eighth, a newborn infant–remains a mystery".
In this gripping and entrancing book, Chandler Burr tackles the life story of Luca Turin, a man with an unusually sensitive nose,and a man obsessed by perfume and smell, a sense that commands a 20 billion dollar enthralling industry of flavour and odors. I was bowled over by Turin, at least the way Burr has described him; a brilliant, feisty, passionate, uniquely creative and completely non-conformist scientist trying to decipher a deep puzzle. Strangely, we still don't know how exactly we smell, and Turin set about to find out just how. Collecting together bits and pieces of biology, chemistry and physics, recent and past, he resurrected a fifty year old theory of smell in an astoundingly novel way. Burr also chronicles the intense interactions Turin had with other scientists, prima donnas in the field, big perfumery company scientists and executives, and the editors of the prestigious journal Nature. Turin was as much of a public person as a private one. In the end, Turin fails to convince most of them of the value of his theory, and ends up publishing his theory in a reasonably good but not blockbuster journal.
I was so impressed by this book that it became the basis for a graduate seminar on olfaction and perfume that I am going to give soon, and I have to really thank Burr for that. These days, I am engaged in thrusting bottles of chemicals under people's noses, and asking them to describe the smell. The book also introduced me to the dazzling and unique world of perfumery and smell in general, a bizzarely interesting mixture of art and science. The exotic sources for perfumery raw materials kept me glued to it and other perfumery books. Whether it was oudh, that lavish material that is obtained from rotten wood eaten by a fungus in Assam, or ambergris, the mesmerising ingredient originating in the stomach of a sperm whale, the world of perfumery abounds with facts which made me gravitate toward learning more. Most of these perfumery materials are fantastically expensive (typically costing more than their weight in gold) and hence the search for synthetic substitutes is an expedient one. Before I made a foray into this world, I was unaware of the fact that perfumers can smell perfume the way a music maestro or composer listens to a symphony. There are 'notes' in every perfume, and a good perfumer can literally dissect each note and characterize it when he smells a new creation. (For example, 'spicy', 'woody', 'minty' and 'green')
The book makes it clear that the perfumery industry is shrouded in secrecy, sophistication, and glamour. This very fact indicates that the creation of new smells is both an unpredictably creative process, and also a matter of trial and error. Because there is no 'objective' way to judge whether a perfume will be wildly popular or not, seductive advertising, big money, and big names are the name of the perfumery game. I remember, that when I got off on the Charles De Gaulle airport in Paris for a transit flight, the first thing I saw was Nicole Kidman's face staring at me from an enormous poster advertisement for Chanel 5., one of the most successful perfumes ever. Unlike the drug industry, where a drug succeeds if it succeeds, the appeal of perfumes is essentially created by the 'commodification of desire', as Noam Chomsky would probably call it! High society, penthouse cocktail parties, and extravaganza are the engines which fuel the perfumery industry. The perfumery capital of the world is surely Grasse in France. In fact, the French are totally obsessed with perfume. After defense and aerospace, it is their third largest money maker.
All this makes perfumery very much an art, and there is definitely a need for a convincing general scientific framework with which one could relate smell to the structure of molecules that constitute it. My uncle works as a perfumer in International Flavours and Fragrances, one of the biggest perfumery companies in the world, and this book served to enhance my appreciation and fascination of the state of affairs, as I recalled intriguing tidbits about smell and chemistry that my uncle has told me many times. Before Turin came on the scene, there was essentially a general paradigm of smell that drove studies in perfumery. It was a mixture of empirical chemistry and a hodgepodge of art and intuition. However, there were gaping cracks in this framework, and Turin decided to come up with a theory that could remedy this situation. Without going into the details, let me say that Turin's theory is very interesting and innovative, and promises possible new understanding in our study of smell. That the science/art of smell has come of age is indicated by the awarding of last year's Nobel Prize to two researchers who worked out the biology of olfaction.
The only possible flaw in this book, is that Burr does only too well in a sense. His eloquent description of many scientific concepts somewhats clouds the real truth behind them in a dazzling display of words and rhetoric. Things are not as simple as they seem, especially in science. So does his description of top scientists' reaction to Turin, and Turin's futile attempts to solicit interest from big perfumery companies. While it is true that the scientific peer review process that evaluated Turin's theory and finally dismissed it can sometimes be quite unforgiving, Burr makes Turin sound like the hero and all others (including last years' Nobel Laureates) as villains, who have come together in a conspiracy clique to prohibit others from overthrowing their pet ideas. That is rather unfair to them. The fact is that with all its flaws, the scientific review process has its merits and it's probably the best we have right now. Most importantly, not all of Turin's results sound as spectacular and unambiguous as Burr makes them sound, and Turin does not provide overwhelming evidence for them. In fact, some of his results are thought to be almost certainly false by a number of distinguished perfumers. When he first proposed his theory, many were convinced that he would win the Nobel the next year. However, as time revealed the overambitious essence of his ideas (no pun intended), people became much more skeptical. After all, Turin has proposed a theory, but perfumery is still very much an applied and empirical science/art, and is the basis for essentially a consumer industry that owes more to mystique and advertising than it does to hard science. Theories are of no use if they are not predictive and cannot make money for the big perfume giants. Most importantly, smell is SUBJECTIVE, and this is a point which keeps hitting home. Unlike the efficacy of a drug, there is no way to judge the character of a new smell. It may smell of mint to one person, sandalwood to the other. A related problem is that our sense of smell is bound by language, by the way we describe odors, and these descriptions turn out to be completely different for similar odors (even seasoned perfumers face this problem). This is a major barrier that has to be surmounted, if there is to be a satisfactory theory of smell. In this respect, Turin turned out to be too ambitious and tried to devise a general theory, without a proper method of evaluation and measurement. In a way, experiments still have to catch up with his theory. He still has a long way to go (not that the other ones are any more predictive; in this sense, Turin is on the same stage as the old stalwarts). Burr does not enumerate the drawbacks of Turin and his theories as well as he should have. Interestingly, the only serious scientific conference that Turin was invited to was a conference in Bangalore organised by the Tata Institute of Fundamental Research (TIFR) (Burr calls it 'India's Los Alamos'). There, he had lively discussions, especially with students in the rustic 'coffee board' cafeteria of the Indian Institute of Science, a place where I myself have lazed about many times when I spent a summer there.
The one feature of this book that stands apart is the spellbinding and exquisite language that Burr uses, quite worthy of its subject, who is a connoiseur in every sense of the word. Scientific facts and theories, tales of perfumes and their creators, the capricious world of perfume marketing, the artificiality and sophistry that inundates the high profile clientele of perfumes, and finally the man behind the book himself; all of these submit before Burr's flourishing descriptions and make engrossing reading. Burr is a master of rhetoric, and his style is very gripping; this is one of the best page-turners that I have come across.
The only thing that can possibly surpass Burr's language are Turin's own descriptions of perfumes and smells in the best selling perfume guide which he wrote. He has an uncanny ability to nail down the smell of anything in the most interesting and unanticipated words. I had never, ever thought that one could describe perfumes this way.
For example, consider this account of a perfume that he wrote:
Feu d'Issey (Issey Miyake)
"The surprise of Feu d'Issey is total: smelling it is like a frantic videoclip of objects that fly past at warp speed: fresh baguette, lime peel, clean wet linen, shower soap, hot stone, salty skin, even a fleeting touch of vitamin B pills. Whoever created this has that rarest of qualities in perfumery, a sense of humour. A reminder that perfume is, among other things, the most portable form of intelligence."
Or this one:
Vetiver (Guerlain)
"One of the rare perfumes so named that do not betray the character of this uncompromising raw material, Vetiver is a temperament as much as it is a perfume, above all when it is worn by a woman. Stoic and discreet, Vetiver scorns all luxury save that of its own proud solitude. At the same time distant and perfectly clear, it must be worn muted and must never allow itself to be sensed except at the instant of a kiss."
Not surprisingly, this book became quite controversial. Scientists and journal editors alike were miffed because of the bad light that it cast some of the big names in smell research in. A group from Rockefeller University published experiments in the well-known journal Nature Neuroscience, that did not support Turin's theory. But they were bound as well by the problem of objectively evaluating smell, and so even their experiments are certainly not the final say on the matter. However, all this backlash is actually a tribute to Burr, who could make his book so attractive and compellingly convincing, that even scientific journal editors needed to take note and criticize it (a rare event indeed for a popular scientific book).
My advice; read the book and enjoy it. It could be a fantastic read. However, don't take Burr's words too seriously and literally. Science is a harsh world, and rhetoric cannot undermine the rough scrutiny that any theory undergoes. One thing is for sure; Turin will be remembered, whether his theory survives or not. It is clear that even if he had not invented his smell theory, he would have still been a very interesting character for a profile. If his theory can be used in a fruitful way, it will be a great and enduring one. If not, at least he should be thanked for inspiring a wonderfully written book. For me, both ways it would be a reward, since the book and Luca Turin introduced me to a new and fascinating world.
The cyanuric acid-melamine doggie
I was reading a 1995 ACR review by the priestley George Whitesides yesterday, and one of the things he talked about was the stunning cyanuric-acid melamine hydrogen bonded system. So I fired up my old Macromodel dashboard, and built up a few of these beautiful symmetrical structures.
But somewhere in the middle, I realised I could do other stuff...
Some bloggers have complained once in a while that they want a pony, iPod, and other such creature comforts. All I can do right now is give them a doggie. Ponies will have to wait; sorry fellas.
Here's the cyanuric acid-melamine doggie
And here it is in its hydrogen bonded glory
Sure, it looks more like some weird hybrid version rather than a pure breed. In fact, it's hard to get everything in exactly the same plane. But there's only so much that one can do with two molecules and their hydrogen bonded potential, which turns out to be a lot actually.
P.S. The OPLS force field sucks for optimization of melamine. Good old MMFF is swell for it though.
But somewhere in the middle, I realised I could do other stuff...
Some bloggers have complained once in a while that they want a pony, iPod, and other such creature comforts. All I can do right now is give them a doggie. Ponies will have to wait; sorry fellas.
Here's the cyanuric acid-melamine doggie
And here it is in its hydrogen bonded glory
Sure, it looks more like some weird hybrid version rather than a pure breed. In fact, it's hard to get everything in exactly the same plane. But there's only so much that one can do with two molecules and their hydrogen bonded potential, which turns out to be a lot actually.
P.S. The OPLS force field sucks for optimization of melamine. Good old MMFF is swell for it though.
The mystical Sir Isaac
One of the favourite tactics of religious people who want to use science as firepower for their arguments, is to proclaim that both Albert Einstein and Isaac Newton were religious. They think that marshalling the tacit support of two dead scientists who are among the greatest in history would help them fight for their cause.
However, there are a number of points that help to refute such disingenuous arguments. In the first place, such an argument is an appeal to authority, which by itself does not provide any 'proof' whatsoever for its justification. Now, as far as Einstein is concerned, it's quite clear that he used 'God' as a metaphor for the ultimate mysteries of the universe, for those awe-inspiring truths in the cosmos which we can't yet comprehend. Uses of the word God or something similar galore in Einstein's famous and oft-quoted phrases and writings, yet to my knowledge, there is not an iota of evidence that he believed in the personal deity which most people associate with the word 'God'. In his later years, Einstein was a strong supporter of Zionism and the creation of Israel, yet, it's clear that even these concerns of his were more humanitarian than religious, and did not attest to any deep deistic Jewish faith inside himself. So, for religious people to claim Einstein as their own is dishonest, and shows a simple ignorance of historical facts. At most, Einstein can be called a spiritual philosopher, but not a religious person by the common definition of the term.
But among all the scientists in history, the genius who appears the most mystical to future generations is Newton. This is partly because of the sheer and astonishing breadth of his imagination, which still defies comprehension. He single-handedly laid the foundations for all future physical science, and also invented the mathematical tools necessary to describe nature. Inspite of the two great achievements of twentieth century physics, quantum mechanics and relativity, we still live in largely a Newtonian world. Purely as a scientist, Newton's abilities do appear mystical and almost magical to all of us. This image of Newton is cemented by the way he lived his life, as a solitary and obsessed man who toiled for months in his laboratory and rooms without once appearing in front of the outside world, as a recluse who was so paranoid about his creations- pinnacles of human thought- that he sought to keep them secret for years, deciding to publish them years later in a burst of revelation. As Alexander Pope said, 'God said, let Newton be, and all was light'.
Religious people's fascination for Newton and their tendency to claim him as their own cannot be entirely disparaged, however. Newton in fact saw himself less as a scientist whose job was to document facts about nature and weave them into elegant theories, and more as a solver of puzzles, puzzles whose clues were laid by God for man to unravel. He saw God as the ultimate riddler, and man as the being whose duty was to lay bare His conundrums. He was a Unitarian, who believed in the oneness of divine existence. All these beliefs of Newton explains his later intense forays into theology and alchemy.
Yet, Newton's life cannot belie the facts. The first fact is, the laws of nature which Newton discovered don't need a divine explanation to justify their elegance, power, and use. The world is governed by the laws that he discovered, and it makes as much sense to ask for the 'laws behind the laws' as it does to ask what was before time happened. Even if we do discover some ultimate laws behind these laws, there is no reason to suppose that those laws would not be mathematical.
The second fact may be harder to digest, but it is also true. Newton's later obsession about alchemy and theology was largely crackpot and nonsense. His reams of writings on religion and theology seem more like figments of a magic kingdom constructed by the mind of a deluded person, although just like in the writings of a deluded person, there are some interesting conlusions that he draws. It is difficult to imagine what made Newton give up his spectacular study of natural law, and start searching for cryptic clues in the Bible. But one thing is for sure, whatever the driving force, it is the products of his scientific studies that have survived the test of time, and guide the behaviour of science in the modern world. Just because Newton was a great scientist does not automatically give him authority over deciphering ancient texts, as some religious people would have themselves believe. One can be exalted in one field, totally misguided in the other, and history has many examples which demonstrate this. Newton the natural philosopher was invaluable to mankind, but Newton the alchemist and theologian was at worst a deluded mortal, and at best an amusement of interest to historians, not to mention psychologists.
The third and most important fact that needs to be kept in mind when we talk about Newton, is to accurately guage the times in which he lived. This is perhaps the greatest fallacy which religious people commit, that of analyzing Newton outside the context of his times. We cannot forget that this was the seventeenth century. It was a time when religion did provide the best 'explanation' of many perplexities in the world. Apart from astronomy and mathematics, no other science was well-developed, and both astronomy and mathematics needed the spark of differential and integral calculus that Newton breathed into them to come to life. Newton may have been an extraordinary thinker, but he was probably awed as much as anyone else by the astonishing diversity and workings of life. Biology was not even a formal science then, and absolutely nothing was known about cells and organelles, although Newton's contemporary Robert Hooke would soon coin the term 'cell'. We knew nothing about microbes and their role in disease, about genes, about the transmission of hereditary characteristics. Most importantly, the world had no inkling of the great revolution that would lead us to redefine our origins and existence- the theory of evolution by natural selection, another gigantic intellectual revolution fomented by Newton's fellow Englishman two hundred years later. It is easy, even today, to look at life around us and think that a supernatural being created it. In the seventeenth century, Isaac Newton was as ignorant and smitten by all these mysteries as anyone else, and it was much easier for him and everyone else to believe in a divine provenance for all things in the world.
This was also a time when the grip of religion was very strong, and one also needed courage to make contrary views known. In fact, Newton's views on the oneness of God would have been heretical if he had made them public. The liberal King Charles II made a special concession and allowed Newton to become a fellow of Trinity College, Cambridge in spite of these views. Newton kept his side of the bargain and never published his religious views. That of course did not stop him from poring over ancient texts in private. He believed that theology, alchemy, and the laws of physics, all were manifestations of the divine power of God. But because he said so, that doesn't make them so. Within the context of his times and his genius, one can be sympathetic towards Newton's beliefs, but that says nothing about the facts, which prove that the laws of physics do not need to be combined with theological views in order to attain consistency.
Lastly, the most important and simplest truth about both Newton and Einstein cannot be forgotten; they might have even had beliefs akin to religious ones, but they chose to marshall their intellect and energies to unraveling the mysteries of the universe through science and not religion. Newton may have turned to religion in his later life, but as noted above, for him, his religious excursions were a natural extension of his scientific excursions. As for Einstein, he never gave up his scientific pursuits, although God continued to be a common metaphor in his writings.
Einstein and Newton; the stature of both these men was such and their creations were so lofty, that one cannot help apply religious or spiritual connotations to them. But it should never be forgotten that they looked towards science, not religion, as a means to understand the universe and our place in it.
As for being in awe of the universe, the one fact that the atoms that you and I are made up of were manufactured billions of years ago in furnaces in the innards of blazing and dying stars is much more profound and spiritual for me than contemplating a deity whose existence is questionable by any standards.
However, there are a number of points that help to refute such disingenuous arguments. In the first place, such an argument is an appeal to authority, which by itself does not provide any 'proof' whatsoever for its justification. Now, as far as Einstein is concerned, it's quite clear that he used 'God' as a metaphor for the ultimate mysteries of the universe, for those awe-inspiring truths in the cosmos which we can't yet comprehend. Uses of the word God or something similar galore in Einstein's famous and oft-quoted phrases and writings, yet to my knowledge, there is not an iota of evidence that he believed in the personal deity which most people associate with the word 'God'. In his later years, Einstein was a strong supporter of Zionism and the creation of Israel, yet, it's clear that even these concerns of his were more humanitarian than religious, and did not attest to any deep deistic Jewish faith inside himself. So, for religious people to claim Einstein as their own is dishonest, and shows a simple ignorance of historical facts. At most, Einstein can be called a spiritual philosopher, but not a religious person by the common definition of the term.
But among all the scientists in history, the genius who appears the most mystical to future generations is Newton. This is partly because of the sheer and astonishing breadth of his imagination, which still defies comprehension. He single-handedly laid the foundations for all future physical science, and also invented the mathematical tools necessary to describe nature. Inspite of the two great achievements of twentieth century physics, quantum mechanics and relativity, we still live in largely a Newtonian world. Purely as a scientist, Newton's abilities do appear mystical and almost magical to all of us. This image of Newton is cemented by the way he lived his life, as a solitary and obsessed man who toiled for months in his laboratory and rooms without once appearing in front of the outside world, as a recluse who was so paranoid about his creations- pinnacles of human thought- that he sought to keep them secret for years, deciding to publish them years later in a burst of revelation. As Alexander Pope said, 'God said, let Newton be, and all was light'.
Religious people's fascination for Newton and their tendency to claim him as their own cannot be entirely disparaged, however. Newton in fact saw himself less as a scientist whose job was to document facts about nature and weave them into elegant theories, and more as a solver of puzzles, puzzles whose clues were laid by God for man to unravel. He saw God as the ultimate riddler, and man as the being whose duty was to lay bare His conundrums. He was a Unitarian, who believed in the oneness of divine existence. All these beliefs of Newton explains his later intense forays into theology and alchemy.
Yet, Newton's life cannot belie the facts. The first fact is, the laws of nature which Newton discovered don't need a divine explanation to justify their elegance, power, and use. The world is governed by the laws that he discovered, and it makes as much sense to ask for the 'laws behind the laws' as it does to ask what was before time happened. Even if we do discover some ultimate laws behind these laws, there is no reason to suppose that those laws would not be mathematical.
The second fact may be harder to digest, but it is also true. Newton's later obsession about alchemy and theology was largely crackpot and nonsense. His reams of writings on religion and theology seem more like figments of a magic kingdom constructed by the mind of a deluded person, although just like in the writings of a deluded person, there are some interesting conlusions that he draws. It is difficult to imagine what made Newton give up his spectacular study of natural law, and start searching for cryptic clues in the Bible. But one thing is for sure, whatever the driving force, it is the products of his scientific studies that have survived the test of time, and guide the behaviour of science in the modern world. Just because Newton was a great scientist does not automatically give him authority over deciphering ancient texts, as some religious people would have themselves believe. One can be exalted in one field, totally misguided in the other, and history has many examples which demonstrate this. Newton the natural philosopher was invaluable to mankind, but Newton the alchemist and theologian was at worst a deluded mortal, and at best an amusement of interest to historians, not to mention psychologists.
The third and most important fact that needs to be kept in mind when we talk about Newton, is to accurately guage the times in which he lived. This is perhaps the greatest fallacy which religious people commit, that of analyzing Newton outside the context of his times. We cannot forget that this was the seventeenth century. It was a time when religion did provide the best 'explanation' of many perplexities in the world. Apart from astronomy and mathematics, no other science was well-developed, and both astronomy and mathematics needed the spark of differential and integral calculus that Newton breathed into them to come to life. Newton may have been an extraordinary thinker, but he was probably awed as much as anyone else by the astonishing diversity and workings of life. Biology was not even a formal science then, and absolutely nothing was known about cells and organelles, although Newton's contemporary Robert Hooke would soon coin the term 'cell'. We knew nothing about microbes and their role in disease, about genes, about the transmission of hereditary characteristics. Most importantly, the world had no inkling of the great revolution that would lead us to redefine our origins and existence- the theory of evolution by natural selection, another gigantic intellectual revolution fomented by Newton's fellow Englishman two hundred years later. It is easy, even today, to look at life around us and think that a supernatural being created it. In the seventeenth century, Isaac Newton was as ignorant and smitten by all these mysteries as anyone else, and it was much easier for him and everyone else to believe in a divine provenance for all things in the world.
This was also a time when the grip of religion was very strong, and one also needed courage to make contrary views known. In fact, Newton's views on the oneness of God would have been heretical if he had made them public. The liberal King Charles II made a special concession and allowed Newton to become a fellow of Trinity College, Cambridge in spite of these views. Newton kept his side of the bargain and never published his religious views. That of course did not stop him from poring over ancient texts in private. He believed that theology, alchemy, and the laws of physics, all were manifestations of the divine power of God. But because he said so, that doesn't make them so. Within the context of his times and his genius, one can be sympathetic towards Newton's beliefs, but that says nothing about the facts, which prove that the laws of physics do not need to be combined with theological views in order to attain consistency.
Lastly, the most important and simplest truth about both Newton and Einstein cannot be forgotten; they might have even had beliefs akin to religious ones, but they chose to marshall their intellect and energies to unraveling the mysteries of the universe through science and not religion. Newton may have turned to religion in his later life, but as noted above, for him, his religious excursions were a natural extension of his scientific excursions. As for Einstein, he never gave up his scientific pursuits, although God continued to be a common metaphor in his writings.
Einstein and Newton; the stature of both these men was such and their creations were so lofty, that one cannot help apply religious or spiritual connotations to them. But it should never be forgotten that they looked towards science, not religion, as a means to understand the universe and our place in it.
As for being in awe of the universe, the one fact that the atoms that you and I are made up of were manufactured billions of years ago in furnaces in the innards of blazing and dying stars is much more profound and spiritual for me than contemplating a deity whose existence is questionable by any standards.
Worst and best
The worst thing that could happen to you after working on a conformational analysis for three months: suddenly thinking that you might have gotten the stereochemistry of one or more of the 11 stereocenters in your molecule wrong.
The best thing that could happen to you after working on a conformational analysis for three months: checking the 11 stereocenters and finding that all of them are correct.
Painful, really.
The best thing that could happen to you after working on a conformational analysis for three months: checking the 11 stereocenters and finding that all of them are correct.
Painful, really.
Inside the "graduate kitchen"...and what I found there
The "graduate kitchen", just like the "graduate lounge" and the "rabbit hole" of "Alice", is a non-existent entity. But you fantasize about it, especially in light of the dismal thing down the hall that tries to approximate it.
Everyday that I trot down the hall into it to heat my lunch or get my daily coffee, I am assailed by familiar smells, that are yet so unfamiliar that even the Flying Spaghetti Monster would not be able to unravel their composition and sources. The dingy place consists of a table with unidentified food scraps on it, a giant something in a corner approximating a fridge, and stodgy white appliance right next to it, apparently the kitchen microwave.
Each one of these objects has its own story. If you open the microwave oven door, you see what looks like an extra layer of insulation, which turns out to be a 1 inch thick coating of food that has been spilled and splattered about it for the last couple of years. But this is anything but disgusting, at least not so if you don't find finely carbonized ash disgusting. That's what that layer looks like, carbon...or something that resembles it. It's not exactly carbon though, because it still has an 'organic' smell, neother pleasant nor repulsive. One dreams of what molecules could be in there...the cure for cancer of AIDS perhaps. Looking at the specks and layers, I had an idea; scientists could use this system as a model system for studying what happens to organisms and organic molecules when they are cast aloft into space and transported over long distances, bombarded by the less than ambient ultraviolet and other kinds of radiation rampant in the galaxy. The specks in the microwave bear witness to this cruel assault; having been fried countless times over by microwaves, they could perhaps be similar to the molecules that arrived after a perilous journey on early earth to sow the seeds of life. Obviously, Fred Hoyle and Francis Crick must have anticipated the modern grad student lifestyle.
Then there's the fridge. Even my home fridge was a great experimental system; the Chinese roommate who vacated the apartment when I came had a crab in there that was at least six months old. Immense benefits of bleach immediately dawned upon me. A similar, but much more exalted, scenario exists in the "graduate kitchen" fridge. There is some black goo on the fridge floor, long since petrified, that reminds me of a liquid alien form in an X-Files episode. Dig deeper if you dare to, and you find foods of different shapes and sizes, that used to actually form a part of international cuisine. It was two years ago that I stuck a notice on the fridge; "Please do not leave food inside for more than a month...or until it starts to stink". I should have realised; especially when it comes to international cuisine, the stink is in the nose of the beholder. Needless to say, I did not want my own gallon of milk to suffer such a fate. That's why I gulp it down within a week, and post a sign saying "Poison, do not ingest" on it to prevent theft. Then there's the top freezer compartment, which tests the resilience and shelf life of frozen dinners more than their manufacturers could have imagined in their wildest dreams.
In the corner of the "kitchen" sit two transparent lunchboxes. I vaguely remember two students long since graduated, once eating lunch from those lunchboxes. I want to inform them that their fungal growth experiment has worked.
But of course, it's the microwave that really interests me. I wish I could scrape off some of those particles of unknown composition and submit them to chemical analysis and NMR. Then at least, my daily visits to the "graduate kitchen" would have become a little colourful.
Having said all this, just like an unpleasant relative, the kitchen becomes part of your daily life, and so actually manages to somewhat endear itself to you. The random journal issues and magazines tossed on the table entice you to no end to want to stay. Some brave souls, including our department chair in the lead, take on occasional tasks of heading a search-and-rescue operation into the kitchen. At least I wipe something when the source of the spill is my lunchbox or mug. But I am not one of those brave souls.
Everyday that I trot down the hall into it to heat my lunch or get my daily coffee, I am assailed by familiar smells, that are yet so unfamiliar that even the Flying Spaghetti Monster would not be able to unravel their composition and sources. The dingy place consists of a table with unidentified food scraps on it, a giant something in a corner approximating a fridge, and stodgy white appliance right next to it, apparently the kitchen microwave.
Each one of these objects has its own story. If you open the microwave oven door, you see what looks like an extra layer of insulation, which turns out to be a 1 inch thick coating of food that has been spilled and splattered about it for the last couple of years. But this is anything but disgusting, at least not so if you don't find finely carbonized ash disgusting. That's what that layer looks like, carbon...or something that resembles it. It's not exactly carbon though, because it still has an 'organic' smell, neother pleasant nor repulsive. One dreams of what molecules could be in there...the cure for cancer of AIDS perhaps. Looking at the specks and layers, I had an idea; scientists could use this system as a model system for studying what happens to organisms and organic molecules when they are cast aloft into space and transported over long distances, bombarded by the less than ambient ultraviolet and other kinds of radiation rampant in the galaxy. The specks in the microwave bear witness to this cruel assault; having been fried countless times over by microwaves, they could perhaps be similar to the molecules that arrived after a perilous journey on early earth to sow the seeds of life. Obviously, Fred Hoyle and Francis Crick must have anticipated the modern grad student lifestyle.
Then there's the fridge. Even my home fridge was a great experimental system; the Chinese roommate who vacated the apartment when I came had a crab in there that was at least six months old. Immense benefits of bleach immediately dawned upon me. A similar, but much more exalted, scenario exists in the "graduate kitchen" fridge. There is some black goo on the fridge floor, long since petrified, that reminds me of a liquid alien form in an X-Files episode. Dig deeper if you dare to, and you find foods of different shapes and sizes, that used to actually form a part of international cuisine. It was two years ago that I stuck a notice on the fridge; "Please do not leave food inside for more than a month...or until it starts to stink". I should have realised; especially when it comes to international cuisine, the stink is in the nose of the beholder. Needless to say, I did not want my own gallon of milk to suffer such a fate. That's why I gulp it down within a week, and post a sign saying "Poison, do not ingest" on it to prevent theft. Then there's the top freezer compartment, which tests the resilience and shelf life of frozen dinners more than their manufacturers could have imagined in their wildest dreams.
In the corner of the "kitchen" sit two transparent lunchboxes. I vaguely remember two students long since graduated, once eating lunch from those lunchboxes. I want to inform them that their fungal growth experiment has worked.
But of course, it's the microwave that really interests me. I wish I could scrape off some of those particles of unknown composition and submit them to chemical analysis and NMR. Then at least, my daily visits to the "graduate kitchen" would have become a little colourful.
Having said all this, just like an unpleasant relative, the kitchen becomes part of your daily life, and so actually manages to somewhat endear itself to you. The random journal issues and magazines tossed on the table entice you to no end to want to stay. Some brave souls, including our department chair in the lead, take on occasional tasks of heading a search-and-rescue operation into the kitchen. At least I wipe something when the source of the spill is my lunchbox or mug. But I am not one of those brave souls.