Yeasts as a model for human diseases


Twenty-three years ago, a seminal publication by Lee & Nurse (1987) appeared in Nature, entitled ‘Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2’. For any young researcher, this publication looks like routine nowadays, but for those of us who were in the field at the time, this came as a major breakthrough. Up to this time – even though J. Monod had already stated that ‘what is true for E. coli is true for the elephant’– demonstrating that molecular details of functional pathways were conserved from one organism to another was neither frequently nor easily done, especially for species as remotely related as yeast and humans. The fact that a human gene was able to complement a yeast mutant defective in the cell cycle definitely indicated that ‘elements of the mechanisms by which the cell cycle is controlled are likely to be conserved between yeast and humans’.

This first experiment was followed by many others and as our biological knowledge increased, more and more data showed that basic cellular mechanisms as well as functional pathways have been totally or partially conserved throughout evolution.

Rather than ‘yeast’ we should use the word ‘yeasts’, because various yeast species have adapted to different physiological niches and followed different evolutionary paths and thus are suitable models for diverse aspects of comparative biology. Saccharomyces cerevisiae has of course been the leading partner and has generated a wealth of biological knowledge on eukaryotic cells, not forgetting its special importance in the study of mitochondrial genetics and biogenesis. However, other yeasts have also contributed to our basic knowledge on more specific points, such as Schizosaccharomyces pombe on our understanding of the cell cycle, Kluyveromyces lactis on the respiro-fermentative metabolism and Hansenula polymorpha on peroxysome biogenesis, for example.

Any complex scientific process has to be simplified first, while also keeping in mind the important traits that are characteristic of it. For this reason, yeasts are wonderful eukaryotic organisms and particularly useful for this simplified approach. They grow fast, are easy to cultivate and cheap to manipulate. Exquisite genetic and molecular tools have been developed and many markers and mutants are available. Saccharomyces cerevisiae was the first eukaryote to have its genome fully sequenced and functionally annotated. This effort, made by an international consortium grouping many bona fide yeast laboratories, has probably contributed most to the field. Because of the good annotation and the fact that fewer and fewer genes are of unknown function, it serves as a reference genome for the annotation of new ones. For all these reasons, several ‘omics’ approaches were developed using S. cerevisiae. This provided an immense wealth of information that has been used to study more complex organisms.

The possibility of deducing human cell functioning from yeast cell studies led to the idea that some human diseases could be studied at the cellular level in yeast in order to analyse their molecular basis. This became even more appealing since many human pathological mutations are localized in genes that often have orthologues in yeast. This cross-fertilization of human and yeast research has been recognized in recent years by several Nobel Prizes in Medicine which were awarded to yeast geneticists: to P.M. Nurse, T. Hunt and L.H. Hartwell for their work on the cell cycle in 2001, and to E.H. Blackburn, C.W. Greider and J.W. Szostak for their discoveries on telomere and telomerase in 2009. Both of these topics are important for understanding and combating cancer.

After 30 years of work along these lines, we thought it important to present where we stand and what the new trends are. This was firstly explored during a session at the 27th International Specialized Symposium on Yeasts (ISSY) held at Pasteur Institute in Paris, in September 2009. This special issue, however, is more comprehensive as we have invited several authors to contribute to it. As a result, the issue covers different topics devoted to approaches centred mostly on understanding and combating diseases with heavy social and economic consequences.

It is apparent that in recent years yeast has been developed as a ‘suitable model to decipher molecular mechanisms involved in a variety of neurodegenerative disorders caused by pathological protein misfolding and deposition’. Hence, the first contributions in this issue relate to prions, Alzheimer's and Huntington's diseases, and the mechanisms of tau aggregation (see contributions by Bharadwaj et al., 2010; Tenreiro & Outeiro, 2010; Vanhelmont et al., 2010; Wickner et al., 2010).

A second topic, for which S. cerevisiae is a particularly well-suited model, deals with the central role of mitochondria in diseases. Studies on this yeast have recently helped to uncover important new aspects of mitochondrial diseases as well as the role of mitophagy (see contributions by Bhatia-Kiššová & Camougrand, 2010; Rinaldi et al., 2010).

Yeast has also been successfully used in the study of various other metabolic disorders, such as the mechanisms of lipotoxicity and its relation to diabetes-2 onset (see Pineau & Ferreira, 2010). Rapid advances in the analysis of global metabolic regulations in yeast uncovered unsuspected links between lipid, protein and energy metabolism that may provide a general framework for future studies in man (see Petranovic et al., 2010).

Yeast has been developed since the late 1980s as a workhorse for the production of human medicines, for example insulin, hirudin and hepatitis B vaccine. More recently, using synthetic biology, new strains were developed for the industrial production of small therapeutic molecules such as hydrocortisone and artemisinin, while promises of whole recombinant yeast cells as candidates for the production of anti-cancer vaccines are highlighted in this issue by Ardiani et al. (2010). Finally, yeast is nowadays also actively developed as a tool for the identification of new drugs and their targets (see contributions of Bidou et al., 2010; Delneri, 2010).

It remains to be seen how these powerful and versatile microorganisms will be used in the future and what will be the next achievements of yeast scientists in this respect. From the recent developments presented here it appears that areas such as neurodegeneration or orphan diseases, for which a profound unmet medical need exists, will be at the forefront.

We hope that this review will be as enjoyable to read as it was for us to edit and, furthermore, that it will stimulate ongoing collaborations between physicians, pharmaceutical companies and scientists of the yeast community at large.