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Thanks to an ambitious
genetic engineering project, a living miniature factory capable of unrivalled
performance has just been created. It is a microscopic unicellular organism,
bakers' yeast, still known as Saccharomyces cerevisiae. Using
just alcohol or sugar, it is now capable of synthesizing a drug, cortisol
(or hydrocortisone). Although this may appear to be simple, it hides a
complex process, the most complex that has ever been reprogrammed in a
living cell. This achievement was made possible through the close partnership
between Denis Pompon's team at the Center for Molecular Genetics of the
CNRS in Gif-sur-Yvette and the pharmaceutical company, Aventis, with the
participation of other partners within the framework of a large-scale
project begun in 1992. This research, with its far-reaching industrial
implications, is published in the February issue of Nature Biotechnology.
It is now available on the journal's WEB site.
This is the biggest and the
most complex genetic engineering project ever developed. A single cell
is now capable of replacing the industrial process used to manufacture
hydrocortisone (also known as cortisol), one of the main human steroids.
This hormone, which is of major pharmaceutical importance, is produced
on a large scale (on the order of several dozen tons per year), mainly
as a result of its anti-inflammatory properties, by a process that is
both costly and long at this time. The first advances made in the search
for an alternative were presented in 1998 but, this time, it is the complete
synthesis chain that has been successfully reprogrammed in the yeast.
This achievement is remarkable in more ways than one. First, the technological
performance deserves mention. Industrial production of cortisol requires
no less than nine steps, including a bioconversion. The manufacturing
of enzyme molecules contingent on the successful completion of all of
these steps thus required the manipulation of fifteen genes of different
origins. Nine of them were introduced by researchers into the yeast from
other organisms; they are of human, animal and even plant origin. The
other part corresponds to yeast genes which had to be modified to control
this assembly and make sure that it functioned coherently with the new
molecules produced. Genetic engineering of this scope is without precedent,
especially since yeast is a fairly evolved unicellular organism that,
contrary to bacteria, has several compartments (eucaryote cells). Researchers
had to deal with this reality since the different stages of the synthesis
process must imperatively take place in separate compartments.
But this achievement is not only a technological feat. It is also of unquestionable
industrial, commercial and environmental importance. The simplification
of this process, after optimisation, will lead to a steep decrease in
production costs. The living factory is therefore simple and self-sufficient:
the recombinant yeasts are exposed to their food source of sugar or alcohol,
in a carefully controlled environment. Left alone, synthesis will follow
the necessary steps to produce the drug which is secreted into the medium
at the end of the process. Result: no pollution, no secondary waste, and
a drug that is highly pure from the beginning.
This research also opens the way for a new "green" type of chemistry
that is more environmentally friendly. Not only could other steroids by
produced by a similar process but why not other types of drugs as well
whose synthesis has been too complex up until now to be tackled by biotechnology?
Some rare plants, the preferred raw material of pharmacologists could
then be spared.
Finally, this research is also exemplary as a result of the choice and
determination of the involved partners. It is the fruit of a close collaboration
between public partners and industrial ones (Hoechst Marion Roussel, followed
by Aventis) that lasted for at least 11 years and was witness to several
industrial mergers.
These results show that France is capable of playing an important role
in this highly competitive field of biotechnology through continuing support
of developed public research.
For more information: http://perso.wanadoo.fr/denis.pompon
Researcher
contacts:
CNRS: Denis Pompon
Tel: +33 1 69 82 36 80
E-mail: pompon@cgm.cnrs-gif.fr
Aventis: Bruno Dumas and Roberto Spagnoli
Tel: +33 1 58 93 28 05 /+33 1 49 91 50 92
E-mail: bruno.dumas@aventis.com
Press contacts:
CNRS: Martine Hasler
Tel: +33 1 44 96 46 35
E-mail: martine.hasler@cnrs-dir.fr
Aventis: François Gros
Tel : +33 1 55 71 08 48
E-mail: Francois.Gros@aventis.com
CNRS – Life Sciences Department
Françoise Tristani
Tel:+33 1 44 96 40 26
E-mail: francoise.tristani@cnrs-dir.fr
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