Interview with Professor Hartmut Michel by freelance journalist Marika Griehsel at the 53rd meeting of Nobel Laureates in Lindau, Germany, 30 June-4 July 2003.
Professor Michel talks about his work on membrane proteins; developing new drugs (4:36); complications with tailor-made drugs (7:46); the problem of finding students for the team (12:40); the role of basic research (14:46); and the unforgettable moment of the discovery (16:58).
Professor Hartmut Michel, welcome.
Hartmut Michel: Thank you.
You’ll have a short talk with us here today. It’s a few years now since you received the prize, in chemistry. What is it today that you have use for in what you discovered at that time or what are you using, on a daily basis, in that discovery, so to speak?
Hartmut Michel: From the discovery mainly it broke down barriers that now we and other people, more and more other people, try to get structural information about membrane proteins. I work mainly all the time on photosynthesis for materials here, for the synthesis here occurs in this plant, but it also occurs in some bacteria in a more simple version and at the time I worked on that simple version it was good pleasure, because these proteins were nicely coloured and it makes fun to work with nicely coloured material instead of this usual whitish protein stuff.
Was it then also easy in a sort of a way to explain what you were doing to make this structure and is it important to be able to explain what you’re doing in a sort of visual way?
Hartmut Michel: I wouldn’t say it’s easy. It depends also to whom you talk, but in general the prize had two major points. One point was that it was the first membrane protein, as I mentioned already, and to crystallise membrane proteins, when I started, was considered to be impossible. There was even a text book statement that it is impossible to crystallise membrane proteins and I thought this statement cannot be true and I worked hard in order to prove the opposite and at the end I was right and it was a lucky coincidence that I worked and I decided to work in photosynthesis, on the heart of photosynthesis, which is in the centre, of course, of the energy conversion which you get from the sun. So all that energy we have, apart from nuclear energy and maybe also a little bit of energy from the deep sea, is derived at the end from the solar energy so this is a very central process on Earth.
And today, you’re continuing to work on the membrane proteins?
Hartmut Michel: I gave up mainly photosynthesis and actually I thought at that time that photosystem 2 is still pretty good to go. Photosystem 2 is the system which converts water into oxygen. And the oxygen is released as a waste product and all the oxygen which you have on Earth is derived from the photosynthesis and this kind of photosynthesis in evolution was established about maybe two billion years ago and I still think from the chemistry, to split water, to take away the electron centre and the proton centre, to take away the oxygen molecule, is a highly interesting reaction but I thought it so complicated that it will not make fast progress and I always told people that I will re-start with this difficult project after my official retirement but for the moment, other people made big progress …
How does that feel, to have given up? You had an idea then you gave it up for something else.
Hartmut Michel: Well, I didn’t give it up. The other point was I knew that other people were going to thermophilic photosynthetic algae and I had the impression that this is certainly the best system to work on it but I didn’t like to push myself into their field of research, so I decided to go to cellular respiration and to try to find out how oxygen is consumed just opposite reaction of photosynthesis, how your body converts oxygen and your food stuff to water and how the energy conservations is done and this is what we started mainly for the moment but this is, I would think, is not at top level in our research and what’s coming up is more medically important receptors. That is the future direction where we go.
You have mentioned that about 80% of the different drugs that are available on the market today for treating different medical disorders or diseases are working on these membrane proteins. What implication does that have on your scientific works and what is it that you want to achieve there in terms of new discoveries?
Hartmut Michel: Oh, actually my personal aim is to understand how these membrane proteins perform their function. What is their mechanism of action? What do they, how do they that? And when you know that, you also have some side, beside, projects and this can be used in uplight research and when you know the structure, say, of a hormone interacting with a receptor and when you know how the receptor converts the message and transduces the method to the other side of the membrane, then you can interact with the message and most of our diseases are simply caused by the fact that the messages aren’t getting from, either there’s no message or there’s a permanent message and when you know how the messages are converted, then you will be able to find compounds which stop the wrong message or which correct the message and this is what drugs in the end do and when we have this drugs knowledge, we should be able to develop new drugs against many diseases which, for the moment, cannot be cured or that the drugs are not specific enough or have harmful side effects.
Could you give us an example where you can see it would be very, very useful for humankind?
Hartmut Michel: There are many, many diseases in the area but we work mainly now is practically each area of application. Asthma, inflammation, obesity, neural diseases … these all defects in the same kind of class of receptors and this class of receptors, it’s about, I said 58% of all drugs act on membrane proteins and about 60% act on one specific … membrane protein, so called G protein carbon receptors and we have not much structural knowledge. The rhodopsin in the eye which converts the light energy which detects the light energy and you use for vision is the same class of molecule. There we have structural knowledge since two years, it’s a related molecule but of course light is a substrate there, light is used there to trigger the reaction but normally it’s chemicals, it’s hormones, it’s neural transmitter for that. Mainly neural transmitters in the brains are used for the communication between the cells so many psychoses and Parkinson, schizophrenia, are caused by disequilibrium in these receptors in the brain and we would like to understand these better.
Do you foresee in the nearby future a situation where there will be more tailor-made drugs, drugs that are specifically for an individual?
Hartmut Michel: Personalized medicine … it’s more complicated.
Why is that?
Hartmut Michel: Because people are not identical, there are some individual differences. You can look most straightforward for the difference in enzymes metabolising drugs. For instance, there is one cancer drug, and actually the drug is prodrug. It has to be activated by enzymes but some people don’t have the enzyme so they cannot convert the prodrug into the active drug, so it doesn’t make much sense to treat these persons which don’t have that converting enzyme, this activating enzyme, with this kind of drug.
So you can take a drug and then you eat something and it will have a different effect on you than it would have on another person, for example?
That is one example and the other example is that many of these enzymes involved in drug metabolism are induced, they are not there if there is nothing to convert, and one example is grapefruit juice and grapefruit juice has many flavonoids and this compound induce enzymes which work for drug metabolism and when you have drunk grapefruit juice, you get these enzymes active. They are not there before, only a very little amount, so they are made and once you have consumed grapefruit juice, then your drug metabolism’s very different then from the day before. This is not only personalised medicine, it’s also medicine from day to day basis and this is difficult to…
And this is knowledge that we’re gaining now, isn’t it?
That’s true, that’s right.
So there were drug companies who were developing a certain drug which they thought could be applied more general but we can see now it can be used or affect people in a different way.
Hartmut Michel: This information is getting clearer and clearer and one instance so far people didn’t at least drug developers didn’t take really into account that there are differences between men and women in metabolism and in the distribution of receptors and now much of the information which we gain are made by knocking out certain genes in mice which means that a mouse can no longer make a certain receptor and, for instance, it turns out if you delete a receptor for a certain hormone, a female mouse survives easily but a male mouse dies and this also would mean if you develop a drug directed against this receptor and which blocked the drug, it would kill the men but the women would survive, yes?
That’s an amazing …
Hartmut Michel: It’s an amazing thing, yes?
That leads me to the kind of responsibility, you have mentioned, for example, that drug companies develop drugs to make money, it’s profit involved, therefore there are places on Earth where people do not receive certain drugs – we can talk about malaria, for example, it’s changing at the moment. In which way could people like you contribute to that discussion or would you like to contribute to that discussion to make it more clear, you know, if there are any responsibilities on that level?
Hartmut Michel: I think for the moment the big drug companies, they are clearly aware of their responsibility and they invest also in the tropical diseases, also malaria and I’m very optimistic that with our current methodology we will be soon able to fight malaria and I think one approach which looks for me very promising which was actually discovered in India is that malaria has the synthesised fatty acids themselves by a mechanism which is very different from the mechanism which your body, my body uses, so malaria has to synthesise fatty acids and when you block fatty acids, as it’s in its synthesis, the malaria causing organism is dead so I’m very optimistic for that. We know all now the enzymes which are responsible, most of the enzymes now and for that, we find out which are essential and I think the chance that we really can fight off malaria is very, very good.
This is enormous challenges. It must be very exciting and how to you go about building your team that you surround yourself with? You have mentioned that you actually had to go abroad to find students of talent that you needed.
Hartmut Michel: This was a special German situation. A few years ago, we had the problems that not many students started science in Germany, especially chemistry and physics. Biology was, though, ok, and on the other hand, due to the investment of public money into biotechnology, the number of positions and jobs, research projects exploded and as a result of these both factors, the number of students passing the system starting a PhD project or becoming a post doc when down dramatically and it was nearly impossible to find a good student two years ago.
How did you go about it?
Hartmut Michel: What I did would be, we made an international advertisement and we intended to invite maybe 10, 20 applicants to Germany and to interview them and at the end it turned out that most promising applicants were all from India, so I invited then 12 of them to a hotel in Bangalore interviewed them there and hired sex of them and they are now with me in Frankfurt and they do very well.
What are the necessary qualities in a team building like that?
Hartmut Michel: Everybody has a separate project or a certain task within the project and when you are assigned a task, you have to think, you have to consider the education of the person, the knowledge of the person and also the behaviour, how the person would fit into a team.
And your role?
Hartmut Michel: My role, I would say mainly I compare it with soccer playing and I’m now the coach, I’m no longer the player.
How do you view the difference between applied and basic science and what role does an institution like Max Planck Institute, where you work, have?
Hartmut Michel: If you look back, all of the discoveries which changed our life, improved our life, come out of basic research, not of applied research and that’s the reason why we have to go on with basic research, especially if you go to biomedicine and you look for single cascades in the body and for using and … molecules, then immediately when you discover and you’re into leukine or something like that or xylocaine which has a function in the body, stimulating the growth of a certain type of cell, then this immediately could become very important in medicine so the gap between basic research and applied research in biomedicine in basic, is very, very small. I shouldn’t even say it’s a gap, it’s a bridge.
And to be working at the institute like this, what is the driving force, so to speak?
Hartmut Michel: The driving force is the best is if people are really interested to get results and to get new knowledge and of course some people try to just to finish a PhD in order to have the title PhD but these are not the type of research students we would have like to have. Some people like to have the PhD chance in order to further their careers in business or somewhere else and we would like really the people who do the research to create new knowledge. They must have a very high motivation and on the other hand I should say in India the conditions are such that they have many, many students but only very few are allowed to go on to PhD thesis so the competition is very, very hard so their motivation to work hard is extreme, I have to say.
Is there a moment working in the lab, working with your wish of discovering new things, which was of major importance to you, that you can’t forget?
Hartmut Michel: In our field it was getting the crystal and especially I clearly remember the summer in 1981, July 1981, when I first discovered the crystal of the reaction centres in my numerous crystallisation attempts. This is number one. The second gap, then, is you have to show what the quality of these crystals is by X-ray crystallography, so when I did the first X-ray photograph and the crystal reflecting beautifully, it was quite clear that I had made the breakthrough and the rest was working it out. So these were the two moments – getting the crystal and showing that they reflect well.
What did you do then? Who did you call? What did you do? Did you get very excited?
Hartmut Michel: No, very excited, in that respect I’m a slow reactor, I’m not immediate jumping.
Not jumping in the air? But you knew that…
Hartmut Michel: It takes time, it takes time to build up, but it was obvious that it was a breakthrough.
And you had proven which was said not being at all possible in the textbooks.
Hartmut Michel: Right.
One last question – in which way did the Nobel Prize change your life, if it did, and would you like another one?
Hartmut Michel: How did it change my life? One point is that I got it at the age of 40 and this is of course pretty early and as a result of that, your lifestyle changes, not your personal life, like how you live at home. Say how you do, because you are now a person of public interest and this means that you are very often invited and people ask you for advice in society and politics, so you end up on many, many advisory boards. Advisory boards, supervisory boards, and you get many, many more requests and as a result of that, for quite some time I only could react, I could no longer act on myself and I would think if I would have gotten the Nobel Prize much later, I would have been a more successful scientist. I would’ve had much more time which I could have devoted to my research, to my own projects.
And that leads up to the other one – is there a driving force to think about a second?
Hartmut Michel: There is no driving force to think about a second Nobel Prize. I would think one is enough.
Thank you very much. Thank you very much Professor.
Hartmut Michel: You’re welcome
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