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EDITORIAL
Yeasts as a model for human diseases
YEAST RESEARCH
DOI:10.1111/j.1567-1364.2010.00693.x
Final version published online November 2010.
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
FEMS Yeast Res 10 (2010) 959–960
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
2010 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
c
960
well as the role of mitophagy (see contributions by BhatiaKiššová & 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.
References
Ardiani A, Higgins JP & Hodge JW (2010) Vaccines based on
whole recombinant Saccharomyces cerevisiae cells. FEMS Yeast
Res 10: 1060–1069.
Bharadwaj P, Martins R & Macreadie I (2010) Yeast as a model
for studying Alzheimer’s disease. FEMS Yeast Res 10: 961–969.
Bhatia-Kiššová I & Camougrand N (2010) Mitophagy in yeast:
actors and physiological roles. FEMS Yeast Res 10: 1023–1034.
Bidou L, Rousset J-P & Namy O (2010) Translational errors: from
yeast to new therapeutic targets. FEMS Yeast Res 10:
1070–1082.
Delneri D (2010) Barcode technology in yeast: application to
pharmacogenomics. FEMS Yeast Res 10: 1083–1089.
2010 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
c
Editorial
Petranovic D, Tyo K, Vemuri GN & Nielsen J (2010) Prospects of
yeast systems biology for human health: integrating lipid,
protein and energy metabolism. FEMS Yeast Res 10:
1046–1059.
Pineau L & Ferreira T (2010) Lipid-induced ER stress in yeast and
b cells: parallel trails to a common fate. FEMS Yeast Res 10:
1035–1045.
Rinaldi T, Dallabona C, Ferrero I, Frontali L & Bolotin-Fukuhara
M (2010) Mitochondrial diseases and the role of the yeast
models. FEMS Yeast Res 10: 1006–1022.
Tenreiro S & Outeiro TF (2010) Simple is good: yeast models of
neurodegeneration. FEMS Yeast Res 10: 970–979.
Vanhelmont T, Vandebroek T, De Vos A, Terwel D, Lemaire K,
Anandhakumar J, Franssens V, Swinnen E, Van Leuven F &
Winderickx J (2010) Serine-409 phosphorylation and
oxidative damage define aggregation of human protein tau in
yeast. FEMS Yeast Res 10: 992–1005.
Wickner RB, Shewmaker F, Edskes H, Kryndushkin D,
Nemecek J, McGlinchey R, Bateman D & Winchester C-L
(2010) Prion amyloid structure explains templating: how
proteins can be genes. FEMS Yeast Res 10: 980–991.
Monique Bolotin-Fukuhara
Guest Editor
Université Paris-Sud
Institut de Génétique et Microbiologie
Bâtiment 400
Essonne 91405
France
E-mail: [email protected]
Bruno Dumas
Guest Editor
Expression Systems
SCP-Biologics
Sanofi-Aventis
13 Quai Jules Guesde
Vitry sur Seine 94400
France
E-mail: [email protected]
Claude Gaillardin
Guest Editor
INRA UR216-CNRS URA 1925
Génétique Moléculaire et Cellulaire
Institut National Agronomique
Thiverval-Grignon 78850
France
E-mail: [email protected]
FEMS Yeast Res 10 (2010) 959–960