Bottlenecks in Proteomics

Let’s start with a joke. “What are three Germans doing that you have put into one room? – Founding an association!” In Germany we have associations for everything in the smallest village. Associations of hen breeders, associations of stamp collectors, associations of local singers, associations of hobby gardeners, associations of wine drinkers, associations of The Kelly Family concert visitors, and so on. Since late 2001 we additionally have the German Society for Proteome Research (DGPF), whose very first founding charter was wrote down on a beer mat (well, we are in Germany, aren’t we).

The foundation of the DGPF by scientists and industry representatives was a reaction on latest market and application movements towards protein research. Germany already has had strong Proteomics (& protein) research when others were still chasing the holy grail Genomics. But – to my impression – it was never really well communicated. So, one major aim of the DGPF will be to improve the international knowledge about the high level of German Proteomics.

But why are researchers and the industry more and more focussed on Proteomics? One of the major disadvantages of Genomics approaches is the missing connection between a gene and its cellular function. The fact that a gene has been sequenced does not give us the cellular function of the gene product. That makes genomic results so difficult to interpret. Even the sequence analysis with bioinformatics tools does not yield the full picture. Additional problems arise through the organisation of the genetic information as well as the fact that only a subset of genes is active in a specific cell at a specific stage.

So, scientists are moving to the functional level, to the gene products, to the proteins. And they developed the new term, “Proteomics”, for the complete set of proteins (functions) of a cell in a specific stage, in analogy to “Genomics” that addresses the complete set of genes (information) of a cell.

Similar to other attempts with a large-scale option in industrial applications (drug discovery e.g.), it will depend on the technology developing and supplying industry if Proteomics will get its chance. When I was doing the research for this article I had the impression that some companies just stuck the Proteomics label onto their existing products. This is neither a solution nor does it really fit the researchers needs. But where are the bottlenecks and what has to be done?

There is a dramatic increase of complexity while switching from the genetic to the functional level. A gene is a gene is a gene. There is slight variation caused by introns and foreign elements as well as expression control. But our scientific thinking is dominated by the “one gene – one protein” paradigm, even since the knowledge about posttranscriptional modifications has shown that it is not just that simple.

With proteins one has to view every single candidate in the context of multifunctionality and networking. In many cases one protein is not just one function. It is part of a high-complex cellular network of interacting and cascading activities. The function of most regulatory proteins for example depends on environment (regarding ‘cellular clock’ and location), posttranslational modifications and interacting partners. As a result one protein might have a couple of functions depending on where, when and with whom it is. This puts Proteomics to trouble.

At first, there are still no powerful technologies for many aspects in large-scale protein research available. Friedrich Lottspeich, head of the protein analysis group at the Max-Planck-Institute for Biochemistry in Munich and DGPF-chairman, said that recent methods exhibit great potential but are not yet ready for the industrial job, in drug discovery for example. There are only few suitable solutions for automation and high-throughput. Early stage MALDI-TOF applications work pretty well, in Structural Proteomics e.g.. But problems with high-throughput sample preparation, low abundant and hydrophobic proteins are unsolved. In Functional Proteomics automated interaction-screens based on the 2-Hybrid, SPR (surface plasmon resonance) or TAP (tandem affinity purification) technologies – that are essential to discover the networking aspect of proteins – are at its infancy. Antibody-based biochips already show the direction.

At second, Proteome research results in huge amounts of data. Corresponding to the higher complexity, Proteomics causes exponentially more data than Genomics does. But drug discovery (and scientific research in common) is not just collecting data, even if one might suspect some scientists to think so. No, the scientific progress depends on results derived by the analysis and interpretation of collected data. And this is getting more and more difficult with increasing complexity.

Finally, the complexity of protein functionality has to be taken into account while moving forward. An attempt to this is the field of Integrated Proteomics that considers various views by the combination of data coming from different approaches and sources. But . this again increases not only the total amount of data to be analysed but also the level of complexity. According to Thomas Franz, head of the Proteomics core facility at EMBL Heidelberg, existing bioinformatics solutions are not able to quantitatively and qualitatively analyse the produced data. This opinion is shared by a couple of colleagues working in the field. Scientific teams are analysing the data manually again because this is more effective and still yields the most meaningful results.

The conclusion is an answer to my question what has to be done. There is a deep need for at least a) large-scale protein research technologies, b) suitable bioinformatics solutions and c) Proteomics-optimised devices.

I am curious about the future development of Proteomics. It might be overrun by other “-omics” in public attention. But I am convinced that Proteomics will contribute important findings to our understanding of how a cell works. And for sure it is and will be a major market for technology suppliers and bioinformatics companies.

Originally published in April 2002 by Inside-Lifescience, ISSN 1610-0255.

Promoting Scientific Excellence in Europe

 In 2003 I had the opportunity to talk to Prof. Dr. Gottfried Schatz, at that time President of the Swiss Science and Technology Council, at the Handelsblatt-conference “Trends in Biotechnology” in Vienna, where Gottfried Schatz had held a lecture about research barriers within Europe.
Gottfried Schatz offensively criticized that the European systems of university education and research funding hinder the development of scientific excellence. In his view, money for research – by working after the principle of discriminate all-round distribution – was too broadly scattered instead of promoting purposefully. Permanent academic positions and the rigid hierarchy structures at European universities were also a thorn in his flesh. Dr. Schatz was an enthusiastic advocate for the introduction of a tenure track system at European universities, and expected it to generate higher flexibility in science and education as well as to give highly qualified scientists clearer future prospects and better chances.
8 years have passed by.
Did things change?
Did the scientific systems really develop?

Dr. Schatz. You are shaking at the pillars of the academic system that got stuck in many Central European countries. You are demanding structural changes as well as a new thinking in the fostering of young people. What feedback do you get from your colleagues and from the industry on your suggestions? How do people receive your criticism?

The support by non-university circles is very positive. The support from university circles is surprisingly up and down. My colleagues in the natural sciences – particularly in the biological sciences – take it predominantly positive. More conservative disciplines – I think of chemistry and mathematics – are rather reserved. And the representatives of the arts subjects and medicine are almost exclusively in opposition.

How do you explain these differences between the disciplines?

It was unfortunately shown that these different cultures – how someone once called it – already drifted pretty far apart from each other. Also, they do not see themselves as part of a common science anymore. Representatives of the arts subjects emphasize again and again that their methods would be different, that they would need the variety of smaller institutes. And they criticize that a tenure track system – as I suggested it – would endanger this diversity.

This thinking results from the structures in those these arts subjects work today to a large extent. They are so strongly split up that they often consist of small kingdoms, which have relative limited contact among themselves. This is not only a disaster for the scientific research but also for the education of young scientists, that in consequence is too much restricted. For example, during their time as PhD students – which can last up to 8 years – many young scientists have only contact to one single supervisor. 100 years before the natural sciences were seen as high specialized and the arts subjects as more broaden. Meanwhile the situation has turned around.

Will the disciplines – as expected – emancipate from each other? What chances for changes do you see?

Practically we could develop larger structures, starting with the academic education. Here the need for broader and intellectually more varying opportunities is unquestioned. The instrument which we suggested in Switzerland are the graduate courses (“Graduiertenkollegs”) – similar to those in Germany -where groups of graduate students are supervised by groups of professors. So each student has at least 2 to 3 supervisors, and at the same time is in contact with a couple of other graduate students. There are various advantages of this system:

  • the time the students need to finish their thesis’ is decreased,
  • the graduate student’s education is more broaden,
  • the students are treated fairer,
  • and there is a much larger, more interesting scientific environment.

At the same time universities will have to think about bigger units – for example departments of cultural sciences, in whose a much more objective and stronger encouragement of young people will take place compared to an institute that just consists of a professor and an assistant.

Now I would like to dare a topical jump. You spoke very much about “excellence” in your lecture at the Vienna conference. You criticized that especially colleagues who are doing the most remarkable things do not get sufficient support and sponsorship. As an example you mentioned that research funds are too broadly distributed and not decently canalized. What are the instruments science, politics and industry could use to back “excellence”?

I think that at this very point all participants of our scientific system need to look after their responsibilities and develop clear principles. Innovation will only take place when hierarchical structures are as flat as possible, and only skills count and not age or establishment. Public sponsorship should be intentionally orientated to scientific top quality and – I frankly use this wording – in an elitist fashion. For example, in a situation of low budgets the traditional proportional shortenings affecting all colleagues to the same extend are wrong. The best should always have sufficient money available to continue their work in a proper way, even when the mediocrity as a consequence is getting few or nothing at all. But to do that requires a huge amount of political courage.

I admire you for saying these things so openly. You are definitely criticizing ideologically shaped social dogmas of the university education. And I could well imagine that others would be probably stoned for such statements.

That would be a worthy martyr death. [laughing] I am convinced that we missed to explain to the public how research really works. Democracy is extremely important – also in science. And flat hierarchies are a basic principle of a democratically functioning science. But democracy does neither guarantee equal talent nor equal success, but just equal chances. Democracy simply is not egalitarianism but has to facilitate the fair promotion of all talents. It is in the public interest to promote innovation by giving sufficient resources to those who are able to achieve innovation. And I believe that this can easily be explained – even to fundamentalists – and is also mostly accepted by politicians.

Please give me the opportunity to return again to the promotion of new generations of academics at this point. I have been particularly surprised – and was also disappointed – about the very reserved reaction of many young scientists with regard to new concepts of the promotion of young people. It is quite understandable that people play a waiting game. But one of the main concerns is: what happens to those, who do not pass the tenure? For our European culture it is hard to accept that every positive selection automatically includes a negative selection. But the idea of giving everyone the basic right to remain at an university is not acceptable for me.

It is thus very important that our non-professorial teaching staff will give up their status consciousness. In Germany, also in Austria but not so much in Switzerland, this is one of the major problems universities have. If we want to give young scientists more rights, then at present we give these rights to the hands of a generation around the age of 40 that is partially much more reactionary than the professors are. And that is the dilemma of every attempt to reform the universities.

Finally, a true improvement of the situation also requires one of the most effective mechanisms of young people’s promotion: early retirements of professors. In the USA people went exactly into the opposite direction and let everyone in his or her position as long as he or she wants to. To my opinion this is damaging for the system and ethically not acceptable.

From your point of view, which European country is the most innovative as regards supporting scientific research as well as young scientists?

Regarding research support the Scandinavian countries, the Netherlands and also Switzerland are very good… followed with some distance by Germany. Regarding the encouragement of young scientists I do not know any European country, that I could give a sufficient mark.

Thank you very much for the interview, Dr. Schatz.

Editor’s Note

This is the English translation of an interview originally done in German language.

Dr. Gottfried Schatz is President of the Science Council of the Institut Curie (Paris), Scientific Councillor of the Institut Pasteur (Paris), and President of the Swiss Science and Technology Council. After receiving his Ph.D. in Chemistry from the University of Graz in 1961, Gottfried Schatz joined the Biochemistry Department of the University of Vienna where he began his studies on the biogenesis of mitochondria and discovered mitochondrial DNA. From 1964 to 1966 he worked as a postdoctoral fellow with Efraim Racker at the Public Health Research Institute of the City of New York on the mechanism of oxidative phosphorylation. After a brief interlude back in Vienna, he emigrated to the USA in 1968 to join the staff of the Biochemistry Department at Cornell University in Ithaca, NY. Six years later, he moved to the newly created Biozentrum of the University of Basel where he and his group elucidated the mechanism of protein transport into mitochondria. Gottfried Schatz is a member of many scientific academies, including the National Academy of Sciences of the USA, the Royal Swedish Society, and the Netherlands Academy of Sciences, and has been awarded the Louis Jeantet Prize, the Marcel Benoist Prize, the Gairdner Award, the Krebs Medal, the Warburg Medal, the E.B. Wilson Medal, and many other honors. He has served as Secretary General of the European Molecular Biology Organization (EMBO), as Councillor of The Protein Society, and as Chairman of many Advisory Boards.

Originally published on February 27, 2003 by Inside-Lifescience, ISSN 1610-0255

Dancing with Yeasts

The fact that the 2001 Nobel Price in Medicine has been awarded to three Yeast researchers should not lead to the wrong conclusion that the Nobel committee appreciated the fight against alcoholism or overweight. In fact without the tasty products of Brewers or Bakers Yeast (Saccharomyces cerevisiae) our lives would be much more healthy but – honestly – less nicer. Coming to the point, the award really recognizes the contributions of Leland Hartwell, Paul Nurse and Timothy Hunt to the understanding the control mechanisms of the cell cycle, the molecular cell division management system.

I myself did research on cell cycle regulation in Yeast in the late ’90s. As a Yeast guy in an innovative scientific environment that deals with frogs, mice and human cell lines you were always seen as an eccentric – and somehow funny – specialist (and it has always been a challenge to explain that my experiments are not related to the Yeast contaminations in the cell culture lab). Later I was glad to have the opportunity to cooperate and to discuss my results with Gustav Ammerer and Kim Nasmyth in Vienna, two other great Yeast geneticists.

Brewers Yeast – for example – is a budding organism (that is why it is also called Budding Yeast). Daughter cells are formed by small buds growing at the Yeast cell surface. This closely resembles the division of mammalian cells resulting in two daughter cells, e.g.. The key issue for the cell cycle now is to synchronize DNA replication with cell growth and division. And vice versa, the DNA replication needs to be reliably inhibited in the case that there is no division. So, the cell cycle is a series of cell functions controlling the whole life span of one cell generation. It starts over and over again until cell aging or other mechanisms stop the propagation. If the cell cycle does not work correctly cells either stop division or have improperly copied chromosomes or propagate uncontrolled. In humans the latter is connected to cancer.

Here the medical relevance of research with Yeasts like S. cerevisiae and Schizosaccharomyces pombe comes in. Yeasts as model organisms for the understanding of common functions in eucaryotic cells. Yeast cells as easy to cultivate mini labs offering research opportunities as regards fundamental cell activities that are too difficult to study in higher cells with their much more complex regulation networks. Well, if we have learned something about cell cycle regulation in Yeast during the past years then that it is even pretty complex in this very simple organism. Today we know a tight network of internal and external signals including the cell metabolism as well as the cytoskeleton. It looks like that there is not just a simple ‘clock’ but a whole system of communicating proteins with checkpoints and feedback loops. We can use these findings in Yeast to look for homologies and similarities in higher organisms. By comparing functionally known Yeast genes and proteins with the human genome and proteome we will be able to identify new research objectives as well as putative pharmaceutical targets.

To my view this “Nobel Prize for Yeast” is an appreciation of the role of model organisms in modern biomedical science. Understanding them leads to a faster understanding of the molecular basics of cellular malfunctions in humans. As a Yeastman still carrying small buds in my heart I congratulate the Nobel committee on its decision.

Originally published in November 2001 by Inside-Lifescience, ISSN 1610-0255.