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CNRS gold medal

Genome Pioneer

Jean Weissenbach is one of the world's leading geneticists. For the past 15 years, his work has led to giant leaps in our understanding of genomes and revolutionized human genetics. It is for this outstanding work that he has just been awarded the 2008 CNRS Gold Medal.

weissenbach

© C. Lebedinsky/CNRS Photothèque


A distinguished French doctor, the late Jean Bernard, referred to him as science's own “Vasco da Gama.” But the vast, unexplored world that Weissenbach has helped discover is actually incredibly small and quite close to home: it consists of the 3.5 billion “letters” that make up the human genetic code.1 Yet the 62-year old researcher, head of the Genoscope2–the French National Sequencing Center–in Évry, is not a fan of such grandiloquent comparisons. Though of a sober and discreet disposition, Weissenbach has nevertheless given in to the media frenzy that followed his CNRS Gold Medal award. “With over 500 publications in major international journals, he is one of the world's top two or three researchers in this field,” says Arnold Migus, CNRS director general. In his office at the Genoscope, Weissenbach looks back at his career and remembers his first steps in science.

A Sequence of Events
The young Weissenbach used to spend time in the back room of his father's pharmacy, smelling the flasks and powders, and later helping make up ointments and other prescribed medications. So when he left school, he didn't think twice about joining the faculty of pharmacy. Yet the world of research looked far more exciting. Especially back then, in the early 1970s, after molecular biology had really taken off with the discovery of the structure of DNA,3 the molecule of which chromosomes are made and the carrier of genetic information.
So while pursuing his pharmaceutical studies, Weissenbach also followed courses in biochemistry, molecular biology and genetics. After his PhD, and a post-doctorate at the Weizmann Institute in Rehovot, Israel, he continued his work at the Pasteur Institute in Paris. “From 1982, I worked on human sex chromosomes,” he recalls. Four years later, he drew up the first map of the Y chromosome, where he localized the region that contains the gene responsible for sex determination. He was also the first to show that in humans, during the production of gametes, there is an exchange of DNA between the X and Y chromosomes.4
But these were only his first successes. He dreamed of creating a tool that would help identify the genes responsible for genetic diseases. And he had an idea. “I wanted to use markers, called microsatellites,5 which can be used to accurately pinpoint positions along the entire length of the genome to draw up a high resolution map of it,” Weissenbach explains. Convinced that he was onto something, Daniel Cohen and Jean Dausset, from CEPH,6 put a laboratory at his disposal. This promising work was subsequently funded by the French Muscular Dystrophy Association (AFM), and in 1992, Weissenbach obtained an initial genetic map that was published in Nature. “This garnered more attention than I expected,” he comments. Scientists from all over the world were soon making use of the map, which was successively improved in 1994 and 1996. In only a few months, they had already located a large number of the genes responsible for hereditary diseases. The impact was considerable. Weissenbach, who was awarded the CNRS Silver Medal in 1994 for his entire work on the genome, became for several years one of the researchers most frequently cited in the world's scientific literature.

Spelling Out the Genome
Soon after, in 1996, the French government called upon him to take part in what was to be dubbed the “Apollo Program of biology.” Its mission was to read all the “letters” in human DNA. This was an old dream back on the agenda again, now that the genetic map had provided the reference points needed to untangle and penetrate the complexity of the genome, where, amazingly, a mere 2% of the “letters” correspond to genes.
To participate in the international “Human Genome Project” public consortium, the French government set up the Genoscope (see box) with Weissenbach at the helm. This was a good choice: his team, in charge of chromosome 14, had no problems completing the job, and the entire sequence was published in 2003. It was a task of titanic proportions. And also a genuine battle for science and free access to knowledge. For, as Weissenbach recalls, “the American scientist Craig Venter was at the same time working on an identical privately funded project, with the objective of selling access to the data. This kind of privatization seemed very dangerous to us. Only large private corporations would have had access to the data–and this would have meant a considerable slowdown for science.” Meanwhile, in 2000, the researcher also produced the first reliable estimation of the number of our genes: a mere 30,0007 instead of the 100,000 that had been assumed until then. Astonishingly, that number turned out to be less than the one for paramecium, a single-celled microorganism that boasts 40,000 genes, or a grain of rice, which has 37,000. “Since that period, I've turned the page of human genetics,” Weissenbach explains. Discoveries are still coming thick and fast, but in other fields. The Genoscope is in particular carrying out–either alone or in partnership–the sequencing of the genomes of the anopheles mosquito (the vector of malaria), the tetraodon pufferfish, paramecium, rice, and the grapevine, a fitting choice for this enthusiastic wine-lover. But always in need of new challenges, this independent, visionary, and pragmatic scientist has recently redirected his research towards organisms that have without reason been neglected: bacteria. And yet, some microbes that break down wastes play a key role in the planet's ecology. Understanding them better, gene by gene, could lead to all sorts of applications, especially with regard to the environment–making chemistry cleaner or destroying pollutants. “I believe that the life sciences can contribute a great deal to chemistry,” he stresses. “I hope that the prestige that comes with the CNRS Gold Medal can help me work in this direction and encourage others to do likewise.” Obviously, the subject is close to Weissenbach's heart. And before he finally retires from science, he has every intention of doing as brilliantly in this field as he has in all the others.

Charline Zeitoun

Great advances in Genetics

Weissenbach's work has decisively changed our approach to the 6000 or so genetic diseases in existence. Sequencing (see illustration) has provided geneticists with a means of directly detecting gene mutations responsible for these illnesses. To this day, nearly 2700 of these genes have already been identified. This search continues, and is constantly breaking new grounds. It presently also includes the so-called multifactorial diseases, like diabetes, obesity, cardiovascular diseases, cancer, and so on, which are not only the result of a faulty gene, but also subject to external (environmental, etc.) factors. These discoveries were also a first essential step towards developing prenatal diagnostic tests. And with regard to the numerous ethical questions this raises, Weissenbach has always been reassuring: “Fears about eugenics are founded, but should be put into perspective. A genotype that predisposes towards a disease doesn't guarantee that illness will ensue, and can even protect the bearer from another disease. In fact, there is no ideal genome.”
So what comes next? Once the genes are identified and the diseases detected, will we be able to cure patients? Unfortunately, the answer is not yet. We are still unsure of how to act on genes in that way, and proficiency in genetic therapy is still a long way off. “There are many things we still need to understand,” adds Weissenbach. “There are many genes whose functions are not yet known, and we still don't have a full grasp of how a cell works. To forge ahead into genetic therapy with such limited knowledge is premature.” Yet overall, the fundamental progress made in genomics constitutes per se a major advance in our understanding of living systems and their complex mechanisms.
C.Z.

dna

© S. Landel/CNRS



 

Genoscope, a Major French Facility

The Genoscope was the first facility used for large-scale biology in France. Set up in 1997 in Evry, south of Paris, the Genoscope successfully accomplished its first main mission in 2003 with the Human Genome Project. Today, it continues to meet the French academic community's needs for large-scale sequencing. Whether dealing with microbes, animals, plants, or humans, most large-scale projects for genome analysis in France of scientific, medical, or economic importance are carried out there. As Weissenbach further explains, “it lets us keep up with state-of-the-art techniques in the field of sequencing and sequence analysis.” This is notably due to the development, on site, of the computing methods that are necessary for the analysis and comparison of genomes. This computer research is carried out within the framework of the Genoscope's Metabolic Genomics research unit, jointly run by CNRS, CEA, and the University of Evry.
C.Z.

 

Notes :

1. Each letter corresponds to a molecule called a base, and the specific arrangement of the four existing bases (A, T, G, C) constitutes the genetic code.
2. Genoscope-Centre national de séquençage (CEA).
3. The discovery of the double helix structure of the DNA molecule (deoxyribonucleic acid) earned James Watson, Francis Crick, and Maurice Wilkins the Nobel Prize in 1962.
4. At that moment, the chromosomes overlap, and if breaks occur in the DNA sequence, segments can be exchanged.
5. Patterns of one to four letters–CA, TTA, etc.–which repeat at least ten times in succession in the middle of an ordinary sequence.
6. Centre d'étude du polymorphisme humain, founded in 1982 by Jean Dausset and coworkers.
7. The figure is currently estimated to be 25,000.

Contacts :

Jean Weissenbach
Genoscope, Évry.
jsbach@genoscope.cns.fr


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