"We are not the end of the evolution"

Manuel Martín Lomas: According to Albert Eschenmoser, currently the chemist of the XIX century closest to current organic chemists is Emil Fischer…

Jean-Marie Lehn: I totally agree

Regarding the "lock and key" concept, it was surprising even for Emil Fischer that it was so successful so early. Immediately Paul Ehrlich introduced this concept in Immunology with the side chain theory. And also some embryologists in the US such as Lillie used the lock and key concept to explain interactions between sperm and cells – cell-cell interaction - in a paper published in 1914 in the Journal of Experimental Zoology.

And he is right. Cells can recognise each other…

Chemically speaking, to understand what was going on with the ferment and the glycosides we had to wait until the 1950s to find some papers on caltrates by Powel and cyclodextrins by Cramer…

There is a little book written by Cramer which was published in 1957 by Springer on cyclodextrins, inclusion complexes. I was trying to convince Peter Gölitz, the editor of Angewandte Chemie, to reprint it again. It is really useful and interesting. Maybe you still can find it in Amazon, it is highly recommendable.

Until the 50's, with these papers by Cramer, but mainly in the 60's with Pedersen's crown ethers, is the time when the organic chemistry community became interested in that.

Yes

And it takes 20 years more until this kind of work is recognised with the Nobel Prize. The Nobel prize recognises the "development and use of molecules with structure-specific interactions with high selectivity"

It's molecular recognition… They could have said that. It could have been linked directly to Emil Fischer.

Then a lot of things happened from the 60's until 1987. Many people played a role and you played a key role.

It took until 1975 or so because the ferment was there. Pedersen was in it quite early, and we came in. Cram entered a little bit later, but he developed his own. But we didn't know each other, we had never met before. So we decided to meet by attending the same meeting. I think it was a Gordon Research Conference. And we met there. I have to say that my former ideas did not come from Pedersen but from a totally different field: ion binding antibiotics, valinomycin. It was discovered by Brockmann in Germany; its structure and synthesis by Shemyakin in Moscow and later on Ovchinnikov and the transport properties of potassium ions were studied in Moscow and by Pressman in UCLA. This was for me the background and specially valinomycin, since at the beginning of our work I wanted to make cyclic peptides because of valinomycin. So for me inspiration was valinomycin. And it's important to recognise this people, they have been a bit forgotten. Because obviously molecular biology is developed, these things are small molecules, there's more chemistry than biology, chemists don't work on it... it is a pity. I knew Ovchinnikov pretty well, I didn't know Shemyakin, I think I met him just once. In fact I was in Moscow three weeks ago and gave a talk at the Shemyakin Ovchinnikov Institute where I met Tatiana Ovchinnikova. I told them that for me that was inspiration.

To begin by the beginning, you did your PhD thesis with Ourisson. That was natural products chemistry.

Natural product chemistry is a fantastic way to learn. I had to do extraction, isolation, then some derivatives, and then physical analysis – NMR was just coming in – so I think for the training is just fantastic. And then I went to Woodward where I worked on this enormous project, B12. At that time, I also was a friend with Roald Hoffman, he's a little bit older, he was just a postdoc, he just finished his PhD with Martin Gouterman and William Lipscomb, and so we were very good friends, I did some computations with him. It was a really fantastic time.

So you have a background of a natural product chemist when you finish your PhD thesis, and then you move to the States to do total synthesis in what at that time was probably the leader in the world.

Yes, Woodward had this image or status already. I was there 1964, that was when Albert Eschenmoser came to Harvard and started the collaboration.

So after these training years, what is the driving force that brings you to the study of inter-molecular interactions?

In some respect, I'll try to say how to come to something. In fact, I did not want to continue at natural products because I do not think you should do your PhD work for all your life. The postdoc work, B12, was the topic of Woodward and Eschenmoser, no way to compete, and that was not my intention. So at the beginning, when I came back to Strasbourg, I first did Molecular Physics. This is not so well known any more, we published in Molecular Physics, we studied molecular motions in liquids. I introduced in Strasbourg Quantum Organic Chemistry, thanks not to myself but to a French guy who was working with Enrico Clementi – the developer of the first ab-iitio program called IB-MOL programme - by then. I thought it was an important field, since I worked with Hoffman on computing, so I knew about it. I had studied Quantum Physics at Harvard, I followed the courses, and we used a French book – Messiah – a Quantum Mechanics book.

So this is quite a change

Yes. But I wanted to do something different, and I was interested in NMR – nuclear magnetic resonance. That was the reason for the physical part. So NMR came back, I used NMR to study molecular motions in liquids, dynamics of conformational processes, ring inversion, nitrogen inversion and things like that and also organic quantum computations. So for four years, until about the mid 70's we published quite a lot on Quantum Organic Chemistry. But this was in parallel with the rest. I think, even it may be difficult, that my motivation was the following: I wanted to study in fact Philosophy because in high school, in my last year, I took Philosophy and Experimental Science. When you study Philosophy, big problems interest you. How could a chemist contribute to the study of these big problems? Philosophy is in the brain, so let's do something there. So I was interested in Neurochemistry. But how do you do that? Either you study Biology, Biophysics and start all over again, or you try to find the way to get into this. I knew that the transmission of the nerving flux was a matter of sodium and potassium gradients and propagation in our membranes. So I said: sodium-potassium is something small, something for chemists. But there must be proteins/compounds in the nerve membrane that can distinguish between sodium and potassium, two ions very close in the periodic table, just different in size, same charge. How can they do that? Is it possible to find substances which will transport selectively either sodium or potassium through a membrane? And then came out valinomycin, that's it! It transports potassium in mitochondria very selectively. So let's make cyclic peptides. They are very interesting but not very stable; if you put them in acid or in base, they go. So are there ways to make substances which are more stable and nevertheless selective? Then three things happened: 1) Wilkinson had published a paper on solubilisation of alkali metals in THF using what we now call 12- crown-4 (a cyclic compound with oxygens); 2) there is a paper by Herbert Brown where he used diglyme, and at the bottom of the paper there is a reference or note saying that diglyme probably binds sodium; 3) and then came Pedersen's paper. So my mind was prepared, and when Pedersen's paper came I said "obvious". But you have to be more selective and make better and 3-D compounds. You do not make a ring, a 2-D cavity, but a 3-D one.
To continue the kind of reasoning, when you realise that Na-K are two in series, the problem is: how can you recognise an ion in a collection of ions? So you need molecular recognition, which is based on interactions, between entities, non-covalent, i.e supramolecular chemistry. The first time I worked on Supramolecular Chemistry was in 1978, in two papers: one in Accounts on Chemical Research and another and more detailed one in Pure and Applied Chemistry. In the beginning there were some people objecting, they said "molecular recognition is Biology, not Chemistry". It took 5-6 years for Supramolecular Chemistry to become more accepted.

But the field was mature. In the late 70's we had in the lab some connections with Fraser Stoddart who also came from carbohydrate chemistry and who talked about a similar concept which he defined as extramolecular chemistry or something similar...

Fraser he came along at the mid 70's starting in the field, and another person in Ecuador – David Reinhoudt– with whom I had a sort of competition. A third one was Howard Simmons at Du Pont. In fact, Du Pont had everything to do what he did, but they did not bring it together. Then one lab was Pedersen's and the other was Howard Simmons'. He was a very good friend and gave a talk in Strasbourg in June 1969 and I knew that Du Pont might be the competitor. That very day I knew that our patent on cryptands and cryptase had been accepted so I talked to Howard, who felt slightly disappointed. But he was a good friend. He was among the earliest at that time. Then Reinhoudt came in, because he was in industry at that time, Shell, and he was interested in binding some ions, he used glymes and things like that, so he entered the field of crown ethers.

And later on Breslow...

Yes, Breslow studied a year before that, he studied cyclodextrins for a long time and has a lot of papers. He was in the line of Cramer, cyclodextrins.

In parallel, people like me have been more in the biological chemistry side. In the 50's the first 3-D structures of proteins were published by Perutz and that people. In the 70's also the idea of the carbohydrate-protein interaction based on 3-D structures were also emerging. Those years I had the opportunity to keep contact with Ray Lemieux in Alberta, with important contributions on anomeric and exo-anomeric effects. In the field of molecular recognition, he was quite interested in the interaction carbohydrate-protein, e.g. antibodies and lectins and the role of water. It seems he followed a parallel research line.

Good

What about subsequent developments? Do you feel 1987 as a crucial point?

It was a step. It was of course very nice. It probably meant that the field was being recognised as important. It also induced a lot of more work and many laboratories began to be interested in the area, which started developing. Now for me the main problem – maybe linked to this philosophic background - is self organisation. This is for me the big question. For a chemist, trying to understand how matter can become so complex as living or thinking... that is something that for me is the ultimate frontier. I sometimes try to provoke the physicists regarding the importance of general relativity, quantum mechanics, but what about knowing something simpler like how Einstein or Planck can exist? The general ideas maybe underlying, but what about this question? So this is the big problem Chemistry is facing.
The other day I received a phonecall from a science writer of a high impact journal concerning a paper on big problems in science. Physicists told him they were studying the laws of the universe. Big problem. Biologists were studying the rules of life. Big problem too. And Chemists make molecules and materials, and where is the big problem? I told him, "maybe we have the biggest problem. To understand how is it possible that one can produce the laws of physics, maybe you can produce an entity able to formulate these laws, to think back on each one's origin". It is difficult to understand how is it possible. Some people have an easy answer: there is an entity up there which explains everything". But that is not an answer to the question, it is just putting it aside. It is another way of looking at it, but does not provide an answer.

Do you think that the constitutional dynamic chemistry or the adaptive chemistry might be an important step in this connection?

Yes, That's the next step. The way it happens is the following: the way I came to it – e.g. Jeremy Sanders has made enormous contributions - we have made double helices, and we have made helicates with 2, 3, 4 and 5 metal ions. Some day we mixed these ligands, we added the metal ion and saw what happened. There was self-recognition, they just selected each other. This happens because there is a whole equilibrium and finally thermodynamics direct it to the correct constitutions. And there were some two other cases, this was beginning 90's. This gives the idea that in fact a mixture is richer than something pure provided you have information/instructions to keep the selectivity, to control the process. This strengthens the idea that the dynamics are important.
And another case where the kinetics are slower, we found that are many things along the way which are not isolated or identified. We have dynamic processes where the progressive build-up of the final entity goes through pathways which may be complicated. It is a dynamics system. You realise that you had always taken for granted that supramolecular chemistry having weak interactions is dynamic. We knew that because these entities are not as stable as covalent compounds. But you did not think about using this property. And it is a basic property. For supramolecular chemistry it is just normal.
We decided to do something that organic chemistry hates to do: make molecules that can break. You have mixtures and create diversity. You introduce reversible bonds like imines, sulphides, etc. You conclude that covalent chemistry can also be dynamic. It's dynamic chemistry which resides in the constitution: dynamics of reactions, of motions; Dynamics is intrinsic to the constitution of molecules. The object to look at is dynamics. If you can do that, you can adapt. If you change the conditions, it will change itself. Constitutional dynamics is for structure description; the functional one is adaptive, and that's the important one. So constitutional dynamics it is a sort of an intermediate step between supramolecular and the adaptive. After all, you want systems that will respond to outsides, and if it is dynamic, it can do so.

But the difficult thing is to program the system.

To let it choose what it needs, to adapt. If you add protons, or you add sodium or potassium. It is a response to internal or external changes. For instance, in turn you're a biochemist, we have it done in artificial laminin as normal polymers, but we are now making dynamic peptoids with the hope that even making aminoacids which have functional groups that can be reversibly bind, which is not really peptide but a peptoid (a sort of derivative), with the following idea: if one of the combinations leads to a folded structure of high stability from a mixture of aminoacids of that type we should generate that.

So you are generating a biological function

Yes, the first thing is thermodynamic stability. Function is of course even more complicated. And this could have been important in the origins of life. At the beginning, there was some of dynamics before life existed, some evolution, and this evolution was controlled by these organisational principles that a folded structure, which is more stable than another one, has more chances to be produced. So this is adaptive chemistry, and the next step is evolutive, which is more complicated.

This is a different evolution, it is not Darwinian evolution, it is before

It is pre-Darwinian evolution.

Let's move to more practical and applied things. How do you see the process of self-assembly to produce nanostructures? Now that nanoscience is so fashionable, everybody is doing nanoscience and nanobiotechnology... I do not know in France, but in Spain there's a kind of confrontation between physicists and chemists. Nanoscience gives the answer to physicists, while the "bottom-up approach to nanoscience" is becoming more and more interesting and producing many things that the physicists would not produce. This is in connection mainly with nanobiothings.

Exactly.

So how do you see the field and self-organisation?

For physicists obviously nanoscience in Physics has produced these fantastic objects we have, these computers. I do not have one, I try to protect myself, but when you see these little objects, these iPads, where you are connected to the whole world. It is fantastic. Nowadays, microelectronics and the coming up nanoelectronics have produced fantastic objects which give us possibilities, which we never could dream of. They are made by fabrication. At some stage you might reach a wall where you won't be able to make things smaller any more by fabrication techniques either because it is too small or because it is too slow when it is very small like when you use STM or similar techniques than can do lots of things but it takes hours to do it.
They will invent ways to do it faster, no doubt. But the need to the fabrication may be hitting a wall and become too expensive. So you can ask if it is not possible to take advantage of the power of self-organisation, to let the object make itself.
For the moment there's still some wishful thinking, although we know that we can make layers, you can take images in layers, and make self-assembled layers... So there is self-organisation; so I would say that the most powerful computer we have is the brain, and the brain is self-organised: you don't make it, it makes itself. And its components, the neurones, are much bigger than nano or micro. So in fact the most powerful computer, not in terms of the ability to perform a given operation (for that normal computers are much better), but just to have a completely complex integrated set of operations, that's the brain, which is self-organised. So we should combine this power of matter to self-organise with the programming and try to make in the future objects where you have levels: first you organise something; this creates the scene for the next step, and so on. I do not have answers to that. If you ask me to write down a scheme, I can just write two steps and no more. And this is still very far from the ultimate. I used a tautology: the fact that we exist means that it is possible. We have the answer to ourselves, so let's see how this is possible and science stands when you understand that – nature has created us and but once you understand how does nature function, we can go beyond, and maybe some day we can understand how this happens. You make things much more powerful. You can dream a lot of things, it begins to be Science Fiction. And the question is: So what is beyond our thinking? Is it there something?Can we say beyond biothinking right now? I'm sure it will transform ourselves. Science can give us this power. What will we do? I don't know, but we'll probably do it. And in ten thousand years, I guess we are not the same.

So we are an intermediate step in the evolution.

Voilá, exactement. We are not the end of the evolution. But the next steps in evolution, we can do them. That is also part of the evolution. The understanding of how to do this is also part of the evolution. It is natural to make what people think unnatural things, but everything is part of the universe. So I think the concept of nature and not nature is a stupid idea, you cannot separate. The fact that we do it makes it part of nature, what you produce can only be part of nature.

It is a relative thinking, it depends on where you are. I remember some people working on Biology discussing the future of the Earth because of contamination, etc. They always say the same: everything is nature. When you put some conditions on the system, it evolutes in that direction.

Driven evolution.

So it depends on what you put in the system, how you control the system, which is the program. If you could know how the system will respond to your stimulus, you will know a lot. Maybe our question for the journal, since the background of our discussion is Chemistry, how do you see the future in Europe, where you have worked for many years? Is it there a correct education in Chemistry to be part of the Chemistry of the future? Do the European authorities take the right policy for the future of science in Europe? How do you see it in the real context thinking as a scientist?

I am a strong European, and I didn't move to the States, where I have many offers, because of that. I like to be close to Salamanca, Firenze, Venice, Vienna, London, Amsterdam, Paris... I feel European. And our only chance is to make Europe strong. And present day evolution because of the situation and the crisis, in periods of difficulties people tend to go back into themselves, to separate, to isolate... and it is the wrong thing to do. If we isolate ourselves again, we will have the problems we had in the past. Schengen for instance, which some people would like to question right now, is totally unacceptable, it would be an enormous regression. I once had a meeting in St. Petersburg and had a meeting next in Vilnius. We thought to go first from St. Petersburg to Tallin, rent a car and give some lectures, and drive down to Vilnius. I realise when I rented the car in Tallin, Estonia, that I could have driven to Lisbon with nobody asking anything. Now people don't realise the fact that you can move around Europe freely among cultures, cities, countries... and this is for me is an enormous progress. The currency merging, changing a long-term tradition, is a good example of that change and progress. And young and even older generations are afraid from that. For me Europe is our future, I don't like flags, the only flag I like is the European, which tries to bring people together. Usually a flag tends to separate people from others.

So we have to keep Europe and make it stronger. This is not easy, particularly at this time. But how do you see the European scientific policy?

Some very good evolutions. For instance, ERC (the European Research Council) which has introduced on the European level supporting the research on the basis of a project rather than an institution. We had in Europe a culture, contrary to the US, which had a much better system from which we learnt. It is good to give some basic financing to institutions, so that they can function, but it has to be not enough to do everything, so that people are forced to propose projects which will be evaluated and financed if they are evaluated positively. We know that evaluation is sometimes goods and sometimes not good, but that's the way things are. So I think this introduction of project financing, like the ANR (Agence Nationale de la Recherche) in France, with ERC has changed profoundly the scene in Europe. It has pushed some countries in that direction. The idea of supporting ideas and projects rather than just financing labs is very important.

We also have the system in Spain for more than 20 years now. The EU FPs also have this system with projects. My question is in this direction, now that the ERC is in place. But this is the first time for the last five years that you can fund excellent basic science at the EU level because FP are so applied, so industrially-oriented...

And it is so complicated, so much administration. I never was part of one like that, because it was too much work for just taking care of it. I think we should adapt. This is just because politicians didn't want to give it to scientists. ERC is the closest to having scientists under control. I think once that you have decided that a project is good, you leave it to the people. In the US you get your money and then you do what you want. At the end you evaluate it. And this is the way to do it. To give money, responsibility – later on you are evaluated – and if it is not good at the end, you don't get further money. I think it is a very bad idea to try to control everything step by step. Europe still has too much of that people, a lot of burocracy.

I have experience in some of these projects

Me too, but never as coordinator of the whole thing. Coordinators have so much work! It is a full time position.

So this is something that I think we have to change somehow.

ERC is a very good step, in the right direction. The EU is putting a lot of money, even Americans are astonished. For instance, If you want to attract someone from a foreign country to France, if he's a very well-known scientist, they have a very good chance e.g. to get an excellency chair, which is 1,5 to 2 million €. Then they can apply for a senior ERC, and if they are so good, they will get it. It's another 2,5 million €. It's a lot of money, you don't get that in the US. So our system is really very good. We have to make it work, we have to accept evaluation, we have to accept that some things are better than others. So we have the possibility. And we have to be conscious of the fact that China is coming up very strongly. They have a high number of papers, and the quality is improving enormously and since it is a big country, with 1,2 billion people, they have very good brains there.

And the last thing on education. How do you see the general education in Chemistry now in general? In France you know much better... I do not know if you read, I think it was in January, the first issue of Nature celebrating the Year of Chemistry, George Whitesides wrote the article. He was rather critical with the way Chemistry is going. The main point was that chemists keep in very conventional and traditional areas, they don't take risks, considering that there are very important opportunities outside the traditional frontiers of Chemistry, such as Biology or Health. He was complaining that the chemical community of researchers was very conservative and that the education was also very conservative in the sense that science is becoming more and more interdisciplinary and the education is still very conventional and classic. How do you see this?

I think he's certainly right, I agree with that. We have to look at the borders and interfaces with the other fields. And Chemistry, as many people say, is a central science thus it has many interfaces and each interface can be extremely productive and original. Chemistry has also a core: the development of new reactions, which may be considered as classical but I think it has its total justification. When vitamin B12 was synthesised, there was no metathesis, there was no cross-coupling reactions, they have changed the world of Chemistry. And I think these were very important and there will be future reactions. But how could you ask a chemist to plan for it? It's just making new compounds, some are dull and some can be very exciting. I would say it is good to work on an interface, and that with Physics could describe new materials, new properties and there would be many new materials found: other superconductors, magnetic materials and so on. I agree that the interface is the richest, but we have to have the core, making new reactions, new processes is absolutely necessary, because Biology doesn't tell us about cross coupling, it has not invented metathesis. On the other hand, chemists are very aware of all of that. Let's not complain about that: there are conservative chemists, biologists, physicists. Let's complain enough to push us to really explore these interfaces with Biology, where the complexity of the system is so rich for problems suggested to us; with Physics, where understanding the basic Physics is so important but also making things that you can't necessarily predict. So teaching Chemistry should be more integrated. It's not easy, because it takes time. In addition, it should include more experimental teaching. I feel that attraction of Chemistry is the fact that you can act on matter, to handle products, to make new things. This is the beginning. Teaching technique by putting hands on was introduced by Leo Lederman, the physicist Nobel Prize, in Chicago. They introduced it in France in primary schools to challenge the curiosity. Children might ask you why is a bubble forming, what are the bubbles in champaigne, very complicated problems. When I was in primary school I had Leçons des Choses (Lessons of Things), integrating practical phenomena, asking questions about that, and I think we need to re-introduce that. We need specialists, we need to know about Mathematics, Physics, Chemistry, but we also should have an integrated problem to challenge the curiosity. I think that current power of databanks and computers and Internet is very important. We have to change the way of teaching. Giving a lecture on a specific topic, e.g. reactions of alcohols or acids... you find that on the Internet. What a professor should do is say "You look up in the book, Internet etc. and next time we discuss it". You ask questions, so you come back to Socratic: you try to get out the questions and answer them, so that people have to think about it and not just copy what the teacher is saying and then learn it. You want them to know but to think about. We need to let the databanks to the job of the knowledge. The first thing, you need those data, you have to know things, and you have to work on it so the hardware is provided by all the means we have around but the software is the important thing. Evidently, you cannot have software without hardware, but the software is the way to make it efficient. Teaching should be a way of making people think about matters.

And not to forget, they also have to go to the lab and the experiments...

Of course. And that's expensive. That's one reason for which I had more experiments when I was in high school than now because a) danger, nobody takes any risk any more; and b) it is expensive, budgets are lower. But they are very important for Chemistry and also for Physics.

So thank you very much. I enjoyed it so much.