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Matthias Mann on Telomerase, Obesity, and Moving to Max Planck

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At A Glance

Name: Matthias Mann

Age: 44

Position: Professor of Bioinformatics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, since 1998.

Prior Experience: Leader of Protein and Peptide Group, European Molecular Biology Laboratory, Heidelberg, Germany, beginning 1992

Postdoc and later senior scientist in the Department of Molecular Biology, University of Southern Denmark, beginning 1989

PhD student in physics and chemical engineering, Yale University, since 1984

 

How did you get involved with proteomics?

I did my PhD on electrosprays. I worked with John Fenn and this group that developed electrosprays who one and a half years ago all reunited in Stockholm when (Fenn) got the Nobel Prize. So I’ve been in the field since 1984, and it wasn’t called proteomics then. The proteomics field didn’t exist then. I was originally interested in this electrospray business. I’m originally from Germany and John Fenn had a visiting professorship where I was. We did a project together and he asked me to come to his lab to do my PhD at Yale, and I did that. And so basically, I stayed with this electrospray all the time and used it to develop more sensitive methods, higher throughput methods. And then proteomics started first with 2D-gels, but then it turned [out] to be mass spectrometry based very quickly. And so that’s how I got into the proteomics field.

What projects were you working on back then?

Well, that was really the development and characterization of electrospray. And then we showed for the first time that it could be used for proteins. That’s what people got interested in, because there were a number of techniques that could be used for small molecules, but this was the first technique that you could use for larger things. And that really got everybody excited, and then everybody started to work on this, including myself — I continued to work on this. Then I was at EMBL, the European Molecular Biological Laboratories in Heidelberg in Germany. And there we developed the first algorithm to basically match. When you fragment a peptide by mass spectrometry, then you have to match them to a database, so we developed the first one of those algorithms which was called Peptide Sequence Tag. It was actually the first database that allowed you to search mass spec data against the database. So pre viously, people had been trying to get the whole sequence from the mass spec fragmentation, but this is still even nowadays very difficult. So matching against the database was a lot easier.

Back then, what were people using mass spec for?

They were using it for small molecules, for drug studies and so on. And when they were working with proteins, they were using it for protein chemistry. So for example, companies like Genentech and so on and the big pharmaceutical com panies, they would have mass spec groups, but they would be looking at recombinant proteins. So they would be checking whether they were correct. Whereas when you wanted to study a huge factor involved in some biologic function, you would use Edman sequencing at that time. So only when we could do this database searching and we did some other changes that made it more sensitive, like the nanoelectrospray, then you could use it for really getting something exciting. The first exciting one like that that we got was telomerase. So with Tom Cech we sequenced and even cloned the telomerase. That was in ‘97, using the nanoelectrospray.

Can you go over how you developed the electrospray?

I got into John Fenn’s lab when electrospray was already there. They had used it for small molecules, but not for proteins or peptides. So in the four years I was there, then we developed it more for proteins. I’ve been always interested in these algorithms, so like for this database search, at that time I did this algorithm called deconvolution. When you have an electrospray of a protein you have lots of confusing peaks which are all due to the protein, but couldn’t be interpreted. I developed this mathematical algorithm that showed you the protein as if it had been measured at only one and the correct mass that it was supposed to have. Basically, when you have this confusing data, you keep looking at it and trying to see how you can transform that data.

So one of the first proteins that you solved was telomerase?

Yeah, of the ones that were really important. At the time there was lots of talk about mass spectrometry, but people wouldn’t use it for serious problems. Then when we sequenced telomerase and shortly after we sequenced caspase 8 — that’s one of the key molecules in apoptosis — lots of people were after this protein all over the world. In programmed cell death you have this signaling pathway of caspases that activate each other, and that’s how the cell commits suicide. This was a key member of that signaling pathway, and in terms of proteomics it was important because it was very competitive to get this — everybody was working on this with lots of different technologies, and then we got it due to the nanoelectrospray and the database searching. So that convinced a lot of people that this was now for real.

What have you been doing since then?

Since then, I went from Heidelberg to Denmark in ‘98 and here my lab is half biology and half proteomics, and that’s a little bit different from other proteomics people because most proteomics people, they work on developing the technology better and then they apply it in their collaborations with someone by saying ‘Don’t you want to analyze this interesting problem for me?’ The other group will do the problem, they will do the biology. In my group, at least half the people are bio logists, so we find our own biological problems which are mainly in the area of cell signaling in the diabetes and obesity area. And then we use all the state-of-the-art proteomics methods, but we also have all the biological signaling assays and so on.

How did you get involved in the obesity and diabetes areas?

We were collaborating with the hospitals here, and they are interested in a similar area. And we also became a member of the network in the Boston area, and there are some leading diabetes groups there. We have for some years been working on related projects such as using proteomics methods to see what signaling molecules the fat cells secrete. So that’s of great importance in diabetes and obesity because it’s thought that that signaling goes from the fat cells to the brain, and it’s regulated. The most famous one is the leptin molecule. You’ve probably heard of these leptin mice that if they don’t have the leptin, then they get incredibly fat, and if they are missing the leptin receptor they also get incredibly fat. Proteomics is a very good way to get a handle on [the signaling].

Do you use any kind of a protein chip in these experiments?

No. Our work is really based on mass spectrometry. We try to stay out of the protein chip area, and out of the 2D gel area also. Basically, you go with what you have a specific area of expertise in and what you believe in also. I’ve never been a great believer in 2D gels or protein chips.

Were you surprised when Fenn won the Nobel prize?

I was, actually. I never really thought so much about it, so I was really surprised when I heard that, very pleasantly surprised. It was clear that if a Nobel prize was given for this area, then he should have it for the electrospray, so that was wonderful that he got it and not somebody else. But the fact that they would give it in the first place for mass spectrometry, that was surprising. He’s such a wonderful person. Actually, I didn’t think so much about who would win the Nobel prize. And also, they gave it for ionization of these large molecules, and this we did in the end of the ‘80’s, and since then we’re thinking about completely different things, so if we ever thought about Nobel prize, it would be for more recent things that we did in the last five years or so, rather than 30 years ago. That’s more what one thinks about.

I heard that you’ll be moving to the Max Planck Institute in Munich in about a year. What made you decide to move?

It’s really mainly because it was a really good offer. It was hard money, meaning that one doesn’t have to apply for money all the time. At least for a core group, you will have funding. And it’s a really good institute — one of the best in Germany. It was just an offer I couldn’t refuse. My lab group there will basically be also half proteomics and half biology, and it’ll probably be even larger than it is now. I’m looking forward to it. It should be exciting.

 

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