Nucleic Acids Research, 2003, Vol. 31, No. 14 3869-3871
© 2003 Oxford University Press
EDITORIAL
Claude Hélène was a member of the editorial board of NAR from 1986 to 1997. The following obituary, together with a listing of recently published NAR papers dedicated to the memory of Claude Hélène, can be found on a special tribute page at the NAR website (www.nar.oupjournals.org)
OBITUARY
On the morning of Tuesday, the eleventh February 2003, Professor Claude Hélène died of cancer ending his short but intense and productive life. This is in remembrance of his marvelous personality and his pioneering and outstanding contributions to nucleic acid chemistry. His work ranged from the photochemistry of nucleobases to the investigation of nucleic acid recognition by low molecular weight ligands, oligopeptides and oligonucleotides, as well as to the development of chemical genomics and of applications in functional biology, biotechnology and therapeutics. There is no doubt that Claude Hélène’s dedication and interests in all aspects of nucleic acids had helped shape this rapidly evolving field during the past forty years and will continue to profoundly affect biology, biotechnology and medicine in the years to come.
Claude Hélène was born on 29th January 1938 at Chauvigny (France). He was the youngest child in a family of seven children living in a small country town. As pointed out by Pierre Douzou, his PhD supervisor and a remarkable figure of molecular biophysics in France who was well known for his work in cryoenzymology and the development of relevant techniques, Hélène was a pure product of the French educational system. He enrolled in the Ecole Normale Supérieure de Saint-Cloud (the predecessor of Ecole Normale Supérieure de Lyon) in 1958, where he obtained Agrégation des Sciences Physiques degree in 1962. In the same year, Hélène met his ‘spiritual father’, Professor Charles Sadron, who was a leading figure in polymer physics and chemistry, and for whom the Chair of Biophysics in Muséum National d’Histoire Naturelle in Paris had just been created, for studying biological macromolecules, proteins and nucleic acids. Hélène joined Sadron’s lab and started a PhD thesis on the excited states and energy transfer processes in nucleic acids and their relationship with photochemical reactions taking place in DNA. As Hélène said ‘I fell into nucleic acids and remained there ever since!’
After his PhD in 1966, he went to Orléans at the Institute of Molecular Biophysics where he succeeded Charles Sadron as Director of the Institute in 1974. After 15 years in Orléans (with a short interruption as a post-doctoral fellow with Dick Setlow at Oak Ridge National Laboratory, studying DNA repair), he was elected to the Chair of Biophysics in 1976 after Charles Sadron retired.
The first research program that he proposed to the Muséum dealt with halobacteria. Hélène and his co-workers had investigated in Orléans some aspects of the binding of proteins to nucleic acids especially the lac repressor and aminoacyl tRNA synthetases. They and others had shown that electrostatic interactions played an important role. They knew that some microorganisms could live at high salt concentration but he was amazed when he learned that the internal potassium concentration in halobacteria was close to 4 M instead of 0.15 M in our own cells. And nevertheless these microorganisms controlled the expression of their genes in a specific and efficient way. Hélène and his colleagues had to abandon this because the CNRS, the main French public basic research institution, found no interest in this project: The word ‘archebacteria’ had not been invented yet and studies on extremophiles were not at all fashionable, as they are today. Therefore they came back to more basic research on peptide binding to nucleic acids, investigating the role of aromatic amino acids and their stacking interactions with nucleic acid bases.
Then they discovered a very short tripeptide Lys–Trp–Lys had astonishing properties with all the attributes for specific recognition of apurinic sites in DNA, with the indole ring of Trp replacing the purine base that was missing, together with non-specific electrostatic interactions. In addition to its recognition properties, this peptide was able to cleave DNA at the apurinic site through formation of a Schiff base between the 
-amino group of the peptide and the aldehyde left on the deoxyribose by cleavage of the glycosidic bond. This tripeptide is still probably the smallest site specific ‘enzyme’ for DNA!
Nucleic acids came back to center stage at the Muséum with a research program on the antisense technology that Claude had initiated at the end of the seventies, unaware of the work that Paul Zamecnik had published in PNAS in 1978. No online scientific literature facilities were available at that time to dig out previous publications! In 1980 he set up and headed an INSERM research unit in the Laboratory of Biophysics that continued until the end of 2001.
With the background in physical chemistry, Hélène always tried to apply basic thermodynamic and kinetic principles in his investigations. He imagined that the attachment of an intercalating agent such as an acridine derivative to an oligonucleotide (OligoNucleotide-Bridge-Intercalator, ONBI for short), would have the benefit of the sum of the free energies of both components with an additional entropy loss. Since then, this concept has been widely used in the community of nucleic acid chemistry. In 1987, Hélène and his co-workers had used a 9 nt antisense ONBI which was complementary to part of the 35 nt sequence located at the 5' end of all trypanosome mRNAs, the so-called mini-exon sequence. They had demonstrated that this ONBI was more efficient than the unmodified oligonucleotide to inhibit translation of Trypanosoma brucei mRNAs in a cell-free system. The ONBI had also a specific lethal effect on cultured parasites.
At the end of 1987 came an independent discovery in both Peter Dervan’s lab at Caltech and Hélène’s lab at the Muséum that oligonucleotides could recognize specific sequences on DNA in the major groove. This was the beginning of the story of triplex-forming oligonucleotides (TFOs) and the antigene strategy to control gene transcription rather than mRNA translation by antisense oligonucleotides. Over 15 years, Hélène devoted many efforts in bringing this concept of targeting DNA by purely synthetic approaches to a real application to biological systems: rational design of TFOs, physical chemistry and biochemical characterizations, probing target accessibility in chromatin and demonstrating bioactivity in cultured cells, as shown by his numerous publications and excellent reviews. The new generation of triplex-forming molecules is now used to modulate in a sequence-specific manner gene expression, gene targeting and genomic modifications. It probably will influence biology, biotechnology and therapeutics in the future.
Claude Hélène had more than 450 research publications to his credit which were published in international journals of repute and he had written and edited several books. He was a great orator and his talks were always very inspiring. He was a wonderful teacher and always paid gentle attention to students and collaborators.
Aside from his lifetime achievements in public research and education, he had a second life in the private sector: scientific consultant (1987–1990), then scientific director (CSO, until the end of 1999) of the Groupe Rhône-Poulenc (one of the predecessor companies of Aventis). As written by Dr Frank Douglas, the CSO of Aventis, in a recent letter celebrating his 65th birthday:
‘Through one entire decade, you were the head of the ‘Direction Scientifique’ of Rhone Poulenc, a challenging position, which called for both scientific excellence and supreme leadership. It was your task to oversee, manage and integrate research programs at the interface of the three main sectors chemistry, agro and pharma. Without your political skills, your cross-functional intelligence and your scientific dedication, you could not have succeeded in this position as brilliantly as you have. Your responsibility reached from combinatorial chemistry to gene therapy, from genomics and bioinformatics to molecular biodiversity. You helped to make interdisciplinary thinking a corporate reality: you were an integrator... From 1992 to 1997, you were also leading the ‘Bioavenir’ program, the French national biotechnology program which was a cooperative effort between Rhone Poulenc and all the major research bodies of France. Your leadership was important in this integration process: you were a networker’. ‘An integrator, a networker and a brilliant scientist, these three roles, this triple trait of excellence, are blended into one outstanding personality.’
Until the end of his life, he still served on the scientific board of Aventis, as well as the startup companies Chrysalon then Urogene. On the occasion of his 65th birthday party, Hélène confessed that he had not been reincarnated into the Hindu god Shiva with so many arms and hands that he could take care of many different problems at the same time. Part of his success was due to the devotion of his beloved wife, Thérèse Garestier, who first was his PhD student (assigned by Sadron), was always a support to him scientifically and administratively, so that he could carry out a full 200% scientific life!
Besides the Muséum, Hélène had served on the scien tific boards of many French major research institutions, INSERM, Institut Curie, Ecole Normale Supérieure, Ecole Polytechnique, to name a few recent ones. He had also served on the editorial boards of many international journals. He served as the chairman of Edmond de Rothschild Foundation and the director of the program on ‘Therapeutic Molecules and Targets’ at the Ministry of Research and Technology. In 1988, Hélène was elected as a member of the French Académie des Sciences. He received ‘Prix de la Fondation de la Maison de la Chimie’ (shared with Dervan) and ‘Officier de la Légion d’Honneur’ (the highest French civilian distinction) in 1998, among many other awards. He was conferred the degree of Doctor Honoris Causa by the Université de Liège (Belgium) and by the Katholieke Universiteit Leuven (Belgium).
In July 2001, Hélène was diagnosed with a fatal, widespread bone metastasis stemming from the prostate cancer for which he had been treated two years and half prior. He fought with bravery against the cancer that aggressively invaded his body, but not his mind. With characteristic intellectual curiosity, courage and dignity, he consulted the medical literature and decided his treatment together with his doctors. They implemented, for the first time in France, a novel bone-targeted therapy by combining a bone-homing radioisotope, strontium-89 with a DNA intercalator adriamycin, in order to fight osseous tumor progression and to be clinically responsive to induction of chemotherapy for the patients with systemic metastasis of advanced prostate cancer. During this period, he stayed active, in his characteristic dignity and grace, to make science progress faster and further for the benefit of other future patients.
Just a few days before his passing, an International Symposium was held in his honor at the Muséum National d’Histoire Naturelle (6th–8th February, 2003) with the participation of many worldwide renowned personalities in nucleic acids. He attended every talk and asked pertinent questions as usual. Before the Symposium’s closure, he spoke for forty minutes about ‘The Future of Nucleic Acids at the Muséum National d’Histoire Naturelle’, glancing from time to time at his notes, and exposing his vision of the future development of comparative and functional genomics to better understand Biology, Evolution and Biodiversity at this 377 year-old Institution. Long minutes of thunderous applause and a standing ovation ended his last milestone lecture. Until the end, Claude Hélène had delivered a model of courage and dignity to all his students, collaborators and friends on this ultimate occasion.
As his students and then as close collaborators, we will always have fond memories that we had the opportunity to meet him and the great privilege to work with him. We will always remember this most distinguished scientist and wonderful human being. We already miss him and deeply regret not having the benefit of his direct input and wisdom in science, but we will carry on with his inspiration and legacy.
Contributed by Carine Giovannangeli and Jian-Sheng Sun, Laboratoire de Biophysique, USM0503 ‘Régulations et dynamique des génomes’, Muséum National d’Histoire Naturelle, UMR8646 CNRS-MNHN, U565 INSERM, 43 rue Cuvier, 75231 Paris Cedex 05 France. Email: giovanna@ mnhn.fr and sun@mnhn.fr.
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