I am delighted to be here.
I've had a wonderful time and the most wonderful of all was listening to the last 40 minutes by the previous speaker.
(laughter).
It's a marvellous, marvellous story.
You can learn so much from it beyond the science itself.
And what I want to talk about today, oh it's here already, is just to give a few examples of what I call molecular parables.
For me a parable is something that carries messages beyond the specific content itself.
It's broader, it's to recognise, you sense that, it's a more human thing.
There are parables that we still repeat 2,000 years later.
So, I always thought that teaching by parables has to be a good way to do it, especially for science.
So I'll do 3 of them.
But before I do that I'll have a glimpse of 3 things I thought of talking about instead.
You know this is my first trip to Lindau and you consider all possibilities for your little appearance.
As you've heard my Nobel Prize came quite a long time ago.
You can read about all, all you want, on the web so no point in going into that again.
The first thing I thought about was a theme that connects a bit to what I wander talking on.
There's a cultural gulf often met by and fostered by scientists.
And I love MIT, I've great colleagues, I have 2.
But this just happens to be an irresistible example.
Look here "Mens et Manus", that's mind enhance, wonderful message.
But now you have the scholar and the blacksmith to represent those.
Do you notice anything rather anomalous?
One looks that way, the other looks that way.
They have nothing to do with each other, completely the opposite message from this nice model.
I had an occasion at MIT a few years ago to show this in the presence of the president of MIT.
And I suggested that we should make a transformation, rather simpler than the ones you heard about in the last half hour.
You could just interchange these.
(laughter).
And then it would send a message more correctly, right?
And I was assured that that change would be made, I don't think it's happened yet.
I know at least 1 or 2 MIT people here.
Is it the case that all these years so many people have overlooked this?
Well, there's another moral in that story.
Another possibility I thought about was entanglement.
I published some papers on that last year.
And showing in the case of molecules it's far less mysterious than it's made to be in the usual discussions of entanglement.
But I decided that was too subtle for people.
So, then I thought of another possible topic that was not subtle at all.
Maybe some of you know this book; it would be interesting to talk about this.
But I decided not to, I'll do the glimpses I had listed already.
But I mention these because at 3 o'clock today I'm to meet with young researchers and those other topics are ones you might want to bring up.
So the first example has to do with palytoxin molecule.
You know, as a chemical physicist I'm between cultures.
And I am sometimes in the presence of physicists that say rather disparaging things about chemistry.
One is: "Oh, it's awfully crude; you never do anything very accurately."
And then I sometimes succumb to the temptation to remark:
"Well gee, I've a colleague who has made the equivalent of a measurement better than a part in 10^21. That's respectable isn't it?"
Of course the physicists looked a little bit shaken by that.
"What's that, what's that?" "Oh you wouldn't be interested, it's an organic chemist." "What, what, what?"
And then of course I mention the example of the synthesis of the palytoxin molecule.
It's probably the most poisonous substance we know incidentally.
But Professor Kishi I'll describe has synthesised it.
What's so remarkable about it is that it's a very floppy kind of thing as you see here.
And yet he was able to make just the one isomer of the 2^72 different ones that are possible.
If you don't get it right at each left and right turn you can really get seriously lost.
But 10^21 is a lot.
How did he do it?
So I like to ask my physicist friends who have got into this topic.
How would you do it as a physicist?
And this just illustrates the big cultural gulf between the sciences and an interesting and instructive one I think.
How would you do it?
Well, you might ask for a few zillion mega bucks or something to figure out how to generate molecules in a very exciting way to make all the possibilities.
And then somehow sort out the one in 10^21.
My impression is that's essentially, from what we heard yesterday, the way it was, the possible Higgs boson was searched for.
They said they wound up finding 10 grains of sand or the equivalent there of an Olympic sized swimming pool filled with sand.
This is more or less something like this.
That's a good approach.
Apparently it worked after lots of effort.
But I'll show you a very simple contribution from chemical physics.
There was the key thing to doing this remarkable thing synthesising a molecule like this, more than 400 atoms,
and getting the right structure at each point, each of the 72 points that really were tricky.
Getting what is called the stereochemical isomer.
Incidentally, you've read the thing by now.
The black dots are carbon, the red are oxygen.
This is a little white; it means really an OH group with hydrogen attached.
But there's so many hydrogens we don't put them on if they're only attached to carbon.
And there's 3 nitrogens, blue ones hidden in various places.
So here's Kishi, I've photographed him holding in his left hand an amount of sugar, rather than palytoxin.
Nobody could make that much of it and it would kill more than the whole population of the globe if they were to imbibe it.
And in the right hand a model of the propylene molecule.
Propylene molecule has, if you ignore the methyl group here, is totally flat.
I mean if we just had hydrogens in all these places and hydrogen here too, that would be ethylene, very simple molecule, 2 carbons.
Adding the methyl group raises the question: How are the bonds in the methyl group oriented relative to the double bond and the plain of the rest of the molecule?
Well that's a question that may seem rather trivial but it turns out that bit of information is the key thing.
Kishi is a real wizard, used to get the synthesis correct at all 72 places.
I tell you how he did it.
I put here the correct equilibrium contribution.
I should mention you only have to think about three-fold symmetry here, the methyl group, nothing quite as sophisticate as the five-fold symmetry.
You've heard the wonderful saga about.
But the methyl group is sort of a carbon atom, these 3 hydrogens sticking off in tetrahedral angles between them.
And the adjacent atom here in the double bond, that's what we call a plainer sometimes carbon atom.
You see it has just 3 things attached to it.
So it's a trigonal, we say, carbon atom whereas this is a tetrahedral carbon atom.
So, Kishi knowing this in a way I'll describe in a minute, he could introduce anywhere he needed to a double bond.
That's a standard thing you can do, well known technique in organic synthesis.
And he can do it in such a way that the attaching group that introduces it has a big clunky thing here.
A hydrogen atom there.
And this is something he adds to deliberately when he wants to create another carbon atom going off in this direction.
So by having a big group here and knowing that the hydrogen eclipses is double bond in the equilibrium configuration he knows
that the added group is going to come on this side.
He does it over and over again, 72 times.
Sounds simple right?
Well it's not so simple because you're using macroscopic agents.
You don't individually get to pluck out these molecules and plug it like tinker toys together.
So, whatever you're going to do at some particular site you're working on, you have to be aware of what the reagent you're adding may do at some other site.
So you have to take precautions and build scaffolding and so forth to prevent that.
And make sure the reaction can only occur where you want it.
That's a rather tricky thing.
I would compare this to Beethoven writing one of his symphonies.
Each note very simple, right?
But the combination and the way you have to put them together and all that's what's a masterpiece.
So this is a great intellectual accomplishment to do this.
The organic chemists were astounded because all the cases of stereospecific synthesis of significant big biological molecules
before were cases where you had big rigid ring systems.
So you had nice clear reference cases.
What Kishi did was realise:
"Ah, I can build in my reference configuration any time I need to by taking advantage of this very simple case"
which was a contribution that information of microwave spectroscopy studied in chemical physics.
Ok so how did he do that?
Well, that part was easy.
This is the only thing I'm talking about today where I was personally involved in.
And one reason I decided to mention this story to the young researchers is that it goes this way.
I was a young researcher then, a graduate student.
I got the issue of the Journal of Chemical Physics that had an article on the microwave spectrum of propylene.
No isotopic version so it wasn't completely determinant of the structure of propylene.
In microwave spectroscopy what you deal with primarily are rotational motions of molecules, tumbling in space
and the moments of inertia of course depend on the geometry of the molecule, the masses of the atoms.
So that's the information you can extract from the spectra.
And in this case since we knew from Lloyds work the general structure of propylene,
we could calculate pretty well what would happen if we put a deuterium on the methyl group.
And then you see you have the option, this diagram is a standard thing, you look along the axis of the methyl group and you see on the other side...
If we look at propylene again, you see on the other side if we're looking down this axis,
you'll see something sticking out here which in propylene is a hydrogen atom.
And on the other side a CH2 group with a double bond.
You see looking this way.
You put a disc there and that's what that round circle is in the so called Newman diagram.
So if it's this configuration, there will be a deuterium sitting here.
And if you're adding deuterium in a bulk way, there'll be deuterium that could come there or there.
Only 1 deuterium is added.
So you're going to get 2, you'll get really 3 things, 2 of them have the same spectrum because they're symmetric.
Or if it were this way, if it were stable as had been predicted in a recent theoretical paper before Lloyd's came out.
Of course Lloyd's paper did not have any information about the orientation of the methyl group.
Then you'd have again 2, but they'd be down here and you'd have the deuterium over here.
That would adjust the moments inertia such as the spectral line we're looking at here is this.
Well there are a bunch of spectral lines you can look at and it's all the same, only showing one.
So you can get 99.9999% proof immediately by just measuring and finding these lines for several transitions.
So it's absolutely easy to be absolutely 100% certain that this is the answer.
Well of course as chemical physicists we weren't used to making isotopically substituted molecules.
So we, meaning my office, Larry Kreisler went to Tom Katz, who was another graduate student in the group of R. B. Woodward, a famous organic chemist at Harvard.
And we asked Tom: How do you do this?
And he kindly did some literature research and came back and said:
"Well, you start by purifying dioxane solvent.
That takes about 2 weeks and so forth."
We weren't about to do that.
He didn't realise that microwave spectroscopy has such high resolution that you could have all the different junk and so on floating around.
Only the species we're interested in we could identify completely.
Because when you turn on an electric field, these lines split in a certain way that tells you what the J value is.
And you could be 100% sure.
So we didn't need pure samples.
So in half an hour we started with aldehyde bromide which is the same as propylene with the bromine atom on the methyl group.
We dripped in D2O with a little zinc catalyst, distilled it in a vac line, we had our sample.
In another hour we had the spectrum, knew the answer.
Next morning we reported it to Tom Katz and of course he was flabbergasted.
Well, we thought that was fun, just one night's work.
30 years later I go to hear the lecture by Kishi in which he announces his synthesis.
People came from miles around because this was an historic thing.
Not quite like the possible Higgs boson but pretty exciting.
And the first reference he gives is to the paper that Larry and I published giving the equilibrium orientation of the methyl group in propylene.
I had no idea it would be that interesting or valuable but it turns out it's really universal.
In the whole field of stereospecific synthesis had been enormously expanded because you can do floppy molecules this way.
Well, most molecules are very floppy.
You don't have to rely on special structural things that make it possible otherwise.
So I mention all this because it just involves a methyl group.
But the next story also just involves a methyl group.
I thought this would be a good lead in.
When I was a young faculty member at Berkeley, every young woman I knew was reading this book.
It's actually the 50 year anniversary about its publication.
Sex and the Single Girl, Helen Gurley Brown.
It was a sensation, it sold, I think, 3 million copies the first 2 weeks.
It was a publishing sensation.
Actually, there was very little sex in this book.
It was a little like Stephen Hawkins' "Brief History of Time", you know, you read the first part and then you're not quite getting what you thought you might.
But any rate.
And more recently there's a takeoff on it, Sex in the City, they sort of borrowed the title.
I'm borrowing it too; I'm saying Sex and the Single Methyl Group.
I want you to recognise how important that single methyl group is.
And sex among other things.
We've already seen how important it is if you want to synthesise palytoxin or something like that.
Ok, well here is the essence of the story.
There is a region of the Y chromosome.
I see quite a few people with Y chromosomes here.
It's called the sex determining region.
The Y chromosome is a little pitiful.
It only has room for 35 genes or so compared with the X chromosome which has 2,000 or more at least.
And it seems that there's evidence that historically the Y chromosome used to be a lot larger but it may have shrunk quite a lot with time.
And perhaps it will keep doing so.
I see some XX people smiling a little at that thought.
Anyway, for human XY foetus you can't tell for the first 35 days by ultrasound or anything whether it's going to be male or female.
You can't tell whether it's XY or XX because in terms of anatomy it looks just the same.
But on the 35th day there's this genetic switch that's if DNA operates properly, you get a male baby.
Of course, we know that XY.
But it fails sometimes; about 1 in 50 to 100,000 times the case is it will fail.
And the usual case is a mutation that, if it fails at all, replaces a certain amino acid, a particular site by another one.
And they only differ by a methyl group.
That one methyl group shortens the isoleucine amino acid side group and renders inactive this key gene that's involved in this switch.
So then the baby is viable, born but in terms of anatomy it's female but with XY.
You may have heard years ago there was a big fuss in the Olympics because they had a case like this, infertile.
Ok, well this is a parable because doesn't it make you think a little bit about, gosh, only a methyl group.
A methyl group, here is this one which incidentally NMR, of the sort you heard a wonderful talk about earlier from Kurt and all, demonstrated this.
It's the work of Michael White who is at Carnegie Mellon now.
But just that methyl group.
Now, you're always told, maybe even some of you young people have heard this, that you should tell your kids about the birds and the bees.
And we have people from different cultures here.
Have you the equivalent phrase in your culture?
I learned that it's true in Germany.
You have a similar term to birds and the bees.
No other, so they don't tell you at all about sex.
How many are told something about sex by their parents or someone else?
Astounding.
I'm amazed, how are you planning to contribute to reproduction of our species?
Are you all working so hard?
It makes me wonder, I can't help it.
Ok, what if that methyl group were lacking more often.
You see, nobody tells their kids about the birds and the bees.
Because while birds reproduce somewhat like mammals there are rather big differences.
The egg is one of them.
Bees don't replicate the way mammals do.
You know the bees have an infertile worker class.
Well if this methyl group were lacking more often we'd have an infertile working class.
We'd probably call it XY on their T-shirts or whatever, right.
The XYs, all you XYs, you don't look too worried, but it might happen eventually.
Happen as the mutation kept going.
However, I see some XX people again smiling a little at the prospect but you ought to be aware that because you're XX you're actually at risk.
If certain genes on both of the X chromosomes you have were fully active or expressed as the biochemist says, you would not be viable.
Because that gene generates a certain protein as you know.
That protein is probably an enzyme that controls other things.
And if you double the rates and so on certain things that cause cascades of other, can't go.
So one or the other of your X chromosomes has to be turned off in every cell.
And it's done randomly.
And how is it done?
You don't have to understand science at all, only psychology.
If a professor asks a question like that in a context like this, you must know the answer immediately, right?
Where is the faint voice back there?
A methyl group, it's attached, you attach a methyl group and that deactivates the gene.
This is a very general mechanism; it applies not just to sex but a lot of other things.
It's a big subject but this is the essence of it.
But it qualifies as a parable because it makes you think of what our society might be if the methyl group were not where it usually is.
Ok, so the last of the little things I intended to do...
Oh sorry, I haven't quite finished this subject on the X.
You've heard about testosterone.
Some of you even have an excess, oh excuse me, and oestrogen.
Look at this! This is a trivial difference here.
Any chemist knows you can have either form easily.
This you would get by simply adding the methyl group right there.
You'd turn a trigonal carbon into a tetrahedral carbon.
That's it ladies and gentleman, you're not too different, just a methyl group, yeah.
Ok, think about that.
Now the last little episode is fun.
Recently Yo-Yo Ma, who I am fortunate enough to know personally, approached me and said:
"I want to get a little bit of indigo into my Silk Road project."
How many of you have heard of his Silk Road project?
Boy, this audience is very...
Ok good, we have 10 people.
That's more than usual, no no, much less than usual.
More than 10 years ago Yo-Yo Ma launched this Silk Road project to celebrate and interest people in the great saga of the Silk Road,
the one from India and China all the way to the civilisations of the Mediterranean.
Marco Polo came back with that information and had a huge impact on the development really of our whole civilisation.
And much was traded there and among the things traded were Indigo.
It's a blue dye that is very, very prized, not only because it was very hard to get anywhere any kind of dyes, really good blue dyes.
But it had a mystic quality that in the final stages of dying with it, as you brought it out of solution, it turned magically blue as it came out.
Supernatural kind of mystical thing as so much of chemistry is.
But his idea was since it's now a big section on studying this Silk Road,
not only the music but all the cultural and wars and all the rest connected with it through history.
It's part of the curriculum in middle schools and high schools now, thousands of schools use it.
But we had talked about how to get science more into our general culture.
And he said: "Well, I'd like to have some in the Silk Road.
And indigo should be a good case because it's a molecule that's very interesting and you can tell a story." So, here's a magazine that arrived, resulted from this.
It's Calliope and it's written for 10 to 11 year olds, that's the target.
So that means this won't be too high level for this audience I don't think.
And here this issue has all sorts of chapters, a whole history and all things.
And I have, what he wanted to do, I wrote a little chapter about how the synthesis of indigo totally transformed everything.
For millennia it had involved huge amounts of human labour, very intensive.
And it also led to wars, slavery, all kinds of ugly things.
But when the synthesis actually succeeded as I'll describe it.
It completely wiped out that whole industry within 10 years and it's still, it's almost all made by chemistry today.
And then a little section on what the indigo molecule is.
I wonder.
How many of you know what the indigo molecule is?
Not a single hand, not even among that row of NLs.
Don't be embarrassed, I asked my organic colleagues, they didn't know what it was.
Isn't that a shame?
Because the story I think ought to be told at the start of any organic chemistry class.
It's really very instructive in a general way.
Just as in my first story the punch line was holy smoke.
You know one little bit of key information.
Look what you can do with it, if you've got a wizard like Kishi to take advantage.
Or Beethoven in the case of notes.
Well, here's a typical chem lab in the 1890's.
You notice anything missing there?
There's no sign of the NMR, any spectroscopic apparatus of any kind.
All those people could do was weigh macroscopic amounts of reagents and products, melt and boil, sniff, sometimes taste, drop other crystals in, play games, guess.
That's what they could do.
And look what they accomplished.
These are all figures from the little article that...
I didn't find these figures.
They were put in my article for me.
Really the dye industry which had a tremendous impact in the industrial revolution was launched earlier before the indigo syntheses; I'm going to tell you about.
An 18 year old, another reason I want you to hear this story, accidently found a way to make a very striking purple dye called mauve.
And when Queen Victoria...
He immediately applied for a patent and launched a company before he was 19, I think.
But he made it just from messing around with coal tar which there was great an excess in the 19th century lying around.
But Queen Victoria wore this to her daughter's wedding.
It touched off a firestorm of interest and boosted the dye industry immediately.
There was a great competition in the dye industry between Britain and Germany.
Germany won hands down, within 20 years they had most of the dye industry.
Why?
Historians know why and they've emphasised this, the Germans had better chemistry education than the Brits had.
And may perhaps still be true, I'm not sure.
But at any rate that's a lesson, the parable; it's always nice to have a bunch of lessons.
But how about indigo?
Here is what the molecule looks like.
It has 30 atoms but a physicist ought to like it because the 2 halves are identical, they are just rotated 180 degrees and then connected by a double bond here.
That's the ball and stick kind of model where you can see double bonds and so on.
And this is a space filling model.
You notice it's flat.
You're familiar with probably Pi electrons are all sticking up from the plain.
That's one reason why it packs very strongly together.
Blocks of indigo have been found in sunken ships.
They've been under water for 2 or 3 centuries, absolutely intact still.
You can take it out and still use it.
And it melts very high.
390 degrees centigrade is very high for an organic molecule.
It's just from those Pi electrons, the way they pack and so on.
But that's this beautiful molecule.
Now here's...
we get to the heart of this story.
It was synthesised in the 19th century.
And the dates involved are really intriguing to me.
When I sat down to write an article for 9 year olds about chemistry, I thought gee whiz, you know I can't mess around with any fancy details.
They know about atoms I guess and that's about it.
You know, like the average physicist attitude towards chemistry.
(laughter).
But, so I thought the thing to do is start.
And I think I wrote something like:
"Science abounds in detective stories and a delightful one and a very lucrative one was the synthesis of indigo."
Something like that, it went on.
Well, this fellow in 1865 figured out the correct structure of indigo.
It's like the ball and stick thing, you saw in the previous slide. 1865.
Well, some of you who have taken organic chemistry or even freshman chemistry,
the text books will mention that in the 19th century people were confused about whether, say, water was OH or H2O.
They were not quite clear the difference between atoms and molecules connected together, atoms connected together as a molecule and how many were and so on.
And there was a famous conference, I don't know if it was at another lake which is of course enchanting place.
And an Italian, Cannizzaro, sets people straight.
Finally they can understand.
Not till 1860 did professional chemists have a clear picture of how to really tell you when you had a molecule or you know the correct molecular structure.
You could get the elemental composition in those days by taking it apart cooking it so hard you could separate all the elements and all.
Flame things and you could detect what they were.
But how they're connected together, as I said no spectroscopy, no mass spec, no NMR, nothing like that to help out.
But he figured it out empirically by comparing it with his experiences and guesses.
He had a 6-membered ring, must be attached to a 5-membered.
By 1880 he figured out 2 ways to actually synthesise it.
You could check he had the right stuff by finding out the same melting point and so forth.
But it wasn't commercial viable.
And that touched off literally a gold rush.
Because it was such a valuable material for trade and it still took 17 years to get a commercial synthesis.
100's of chemists were turned loose to do this.
And the BASF company actually invested practically its whole net worth in this one project.
And it succeeded in 1897.
Every physicist knows what happened in 1897.
Any of you not know, I want you to all raise your hands if you know.
Gosh this raising hand thing is a little...
Are you a little too tired to raise your hands?
Have you ever heard of J. J. Thomson and the electron 1897?
Ok, I see some of those gentlemen there nodding.
Yes, they remember now.
So look, it wasn't until 1897 that they even knew atoms had electrons in them.
And of course it wasn't until 1911 that anybody knew there was a nucleus in there with Rutherford.
So these guys didn't know what they were doing.
They just knew there were such things.
Or some of them thought...
other people weren't absolutely sure there were atoms.
This thermodynamic view was...
You don't want to mess around talking about details like that.
But anyway the synthetic chemists knew they were or believed they were and made lots of molecules with their imperfect knowledge but their empirical adventures.
And after 1897 when the 10 years, as I mentioned, totally wiped out the human cooking and all that went on to make indigo in the old way.
And today about 20,000 tonnes are still made every year, most to dye blue jeans.
I see a nice pair of indigo dye blue jeans there for example.
So that's the key story of the second one.
And I want to go on now to...
Oh, if you want any references, there's the palytoxin story.
I published a bit about it in Physics today.
I started out by pointing out to Arthur Schawlow who is a dear friend of mine.
I had a dictum that is now out of date that said that a diatomic molecule has 1 atom too many.
That was the attitude of physicists.
That's changed in recent years, people appreciate molecules more.
But anyway Sex and the single methyl group, here's the work of Michael Weiss and his colleagues who demonstrated that aspect.
And here's a couple of places where I have written about it.
And here's the indigo saga.
If you have any grandkids or whatever, I can recommend the Calliope.
It's a wonderful magazine.
But now I want to draw the final conclusion which I realised for a lot of things, an advice you should all take.
So, let's take it away, let's have the music.
Here's a song by Cole Porter, notice the date, oh goodie, you dance... (laughter and applause).
Hear the words, wait till the song comes.
...you less fortunate mortals, there's just one final message I would give to you.
You all have learned reliance on the sacred teachings of science, so I hope through life you never will decline, in spite of Philistine defiance.
To do what all good scientists do.
Experiment, make it your motto day and night.
Experiment and it will lead you to the light.
The apple on the top of the tree is never too high to achieve,
so take an example from Eve, to experiment... 2 X chromosomes, the first human experimenter, pay homage to her.
...curious, though interfering friends may frown, the curious.
Some of them physicists.
...at each attempt to hold you down, if this advice you always employ the future can offer you infinite joy and merriment, experiment and you'll see.
Thank you.
Applause
I just want to add one comment which I don't really need to because it is obvious to you.
I should have dedicated this song to the previous speaker.
It simplifies it all so well.
Thank you.