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Eckerskorn Applies Space-Age FFE Technology to Protein Separation

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At A Glance

Name: Christoph Eckerskorn

Position: Chief Scientific Officer for Proteomics, Tecan Munich

Prior Experience: Postdoctoral researcher in the labs of Friedrich Lottspeich and Sam Hanash; helped run large-scale proteomics study for startup Top Lab

 

How did you get involved in proteomics research?

That’s just what I learned! My background is in chemistry — I studied chemistry [as an undergraduate at the Maximilians University in Munich] — and my entrance into the life sciences was through my PhD in biology at the Max Planck Institute for Biochemistry in Martinsried. I was studying the molecular differences between acute infectious and persistent infectious viral disease. It forced me to analyze proteins; to see the differences on a protein level. This was ‘85-’89. My first proteomics approach was while working with Friedrich Lottspeich, one of the last PhD students of Pehr Edman, who developed protein sequencing. So I am the grandson of Pehr Edman. At that time we developed methods to identify and characterize electrophoretically-separated proteins, such as using Edman sequencing on Coomassie-stained protein spots directly from blotting membranes.

In ‘86 or ‘87 we were also one of the first labs to digest proteins directly in the gel matrix. The famous in-gel digestion was published in ‘87. This was also [useful] for my PhD because I saw how easy it was to separate proteins in a gel. If you want to compare things, such as infectious and persistent viruses, the only possibility at that time was to separate proteins by chromatography. But proteins from a virus are very huge, and they are all interacting; it was nearly impossible to get them separated. I tried in a weekend to digest those proteins directly in a gel and to compare both. This technology was beautiful so at the time Lottspeich’s lab got many collaborations. So by the time I got my PhD I think I already had 40 co-authorships in peer-reviewed journals. All this was my entrance into what would come to be known as proteomics.

What did you do as a postdoc?

As a postdoc I worked directly in Lottspeich’s lab, and I was a postdoc [for several years] in Sam Hanash’s lab [at the University of Michigan]. I co-authored some papers with him. I think we were one of the first to isolate proteins directly from 2D gels — essentially tumor markers for leukemia. At that time Hanash already had a database of leukemic and non-leukemic lymphocytes and he had a lot of tumor markers. I isolated these tumor markers and [we] sequenced them at the Max Planck Institute in Munich. Finally, I did my habilitation, which is something like a second PhD, where you have to show that you are capable of educating and giving lectures. Then you get a title called private docent, which is essentially the same as an assistant professor. I did this work at the University of M nster in Franz Hillenkamp’s lab. Hillenkamp is the co-inventor with Michael Karas of MALDI-TOF mass spectrometry. There my topic was to directly desorb proteins from the surface of membranes to get the masses of intact electrophoretically-separated proteins. We transferred 2D gels onto appropriate membranes by electroblotting, and analyzed parts of the membrane directly by mass spectrometry, a process called scanning-IR MALDI mass spectrometry. The result was a mass contour plot of a 2D protein pattern.

After that I came back to the Max Planck Institute in Munich, where I became the head of the service facility, succeeding [Wolfram] Schäfer. From there I moved to a small startup company for two years called Top Lab, located in the innovation center for biotechnology near the Max Planck. There we were engaged in one of the first protein analytics or proteomics projects. From there I got the CSO position at Tecan.

What made you move over to Tecan?

Very easy! If you’ve been working for more than 15 years in protein chemistry, then you realize that the current state-of-the-art protein analytics technology [has reached the peak of its capabilities]. To get better insight at the protein level, you need better technology. That means you need access to R&D. That means you need a company or people who know how to automate technology — and automation to me is not only about throughput. This is not the bottleneck in proteomics; to me the bottleneck is reproducibility and sensitivity. If you know the current state of 2D gel technology, then you know that this is one of the negative part of 2D gels — that they are not reproducible and require a lot of effort to run. With Tecan, R&D is a given. Tecan is the number one provider in liquid handling. They know how to automate, they know how to integrate systems, and they have expertise in robotics.

When was Tecan Proteomics actually founded? Were you the first CSO?

I was hired at the end of 2000 [as CSO]. We wrote a business plan, and then we founded Tecan Proteomics, which is now called Tecan Munich. We started operating at the end of 2001, so we are now in our second year. The idea behind [the company] is that we have a strong application focus, through which we can define the technology requirements. We have a staff here of nearly 20 scientists, and we’ve defined what a protein analytics system should look like. We have strong interactions with Tecan’s R&D teams in Switzerland and Austria, who try to manufacture the adequate machines and technologies.

How did you go about acquiring the free-flow electrophoresis technology from Dr. Weber, a company based in Munich?

For me it was quite clear that automation was not going to be enough to address every bottleneck. We also needed new technology, essentially to fractionate cells and reduce the complexity of the samples. [At the time] I had known for a couple of years about a technology called free flow electrophoresis. It’s an old technology — not something we or Dr. Weber invented. I think the first paper published on the technology was in 1959 and there were several efforts to commercialize it, especially in the US. I don’t know the exact number but they spent nearly a billion dollars [trying to commercialize it]. They even shot free flow electrophoresis systems into orbit with the Apollo missions and the Space Shuttle. Weber had his own small company and he solved some of the central problems, involving electroendoosmotic and thermal convection. He had a machine that looked very promising and I had worked with one of his FFE instruments during my time at the Max Planck Institute. I was convinced that this technology would fit perfectly into a proteomics approach and contribute to accessing low abundance proteins. At Tecan we convinced him to work with us and in 2001 acquired his company completely. We stopped [manufacturing] his last product — it was something of a prototype but he had already started selling it — and we [upgraded] it to a really well-running machine.

How are you using FFE? As a preliminary step prior to using 2D gels?

To get better 2D gels you have to automate them, and we’ve done that. [But] an important part of our strategy is not to have just one proteomics platform. There are several aspects to proteomics — you have soluble proteins, membrane proteins, and questions related to cell organelles — and we have a general outline [for dealing with these various aspects]. Sample preparation, fractionation, separation, quantification, processing, and analytics — that’s what you’ve seen on my slides. According to your research needs, we have different possibilities. If you have complex mixtures, you need fractionation. This may be a good chance to use FFE. After that, you need a high-resolution system, perhaps using 2D gels, although not necessarily. If you’ve already somewhat reduced the complexity, then chromatography is an option. We’re working to integrate FFE with MudPIT, which uses multidimensional chromatography. In that case, you take your proteins, digest them, and put them on an ion exchange followed by a reverse phase chromatography column coupled to a mass spectrometer. For me it’s important that there’s not just one way of doing proteomics.

So what is the goal of Tecan Munich?

Our strategy is to provide our customers with solutions, and the solution is more than just an instrument. The customer could just buy individual modules — you can buy the FFE, or in-gel digestion system individually — but I think you need more. You can also buy application development services [from us], especially if you want to analyze a particular cell organelle. We are ready to support those customers on a commercial basis. If you want to integrate, let’s say, FFE, 2D gels, in-gel digestion, and mass spectrometry, you can also buy an integrated platform. But we are not only a platform provider. The solution in principle is an instrument, an application, and the application informatics.

How do you see the market evolving?

In general, the market is very cautious right now. What we see is that big pharma and the others are being very cautious about investing money. It’s not specific to proteomics, but I would say that in the past two years that has changed. The industry has [also] learned from other promising technologies. They see that there was more hype than realistic data, so I get the feeling that the pharmaceutical industry wants to see data on the machines. Instead of saying, ‘Hi, we have something automated here, and we have a new fantastic machine,’ we try to convince people with the data we are producing. We want to show people that when we say we are more reproducible, we can quantify it. When we say we can see low abundance proteins, we have to demonstrate it. But we are very optimistic because in the scientific [community] — in the pharmaceutical industry also — they know they have to analyze proteins.