Name of PI: Prof. Miroslav Radman
Host institution : Institut National de la Sante et de la Recherché Medicale (INSERM)
Research project title: BIOLOGY OF IMMORTAL AND ROBUST ORGANISMS: AN APPROACH TO PREVENTION OF AGING (BIRO)
Letter of support from the Host institution
The principal Investigator
Scientific Leadership Profile
The scientific career of Miroslav Radman makes him “second to nobody” when considering his impact in the area of research of DNA repair, mutagenesis, genetic recombination and the evolution of species. Originality is a trademark of this PI. The discoveries of the mutagenic SOS repair response in bacteria, base excision DNA repair endonuclease III (first discovered DNA damage N-glycosylase for oxidative damage repair), mutagenic trans-lesion DNA synthesis, mismatch repair, genetic barrier between closely related species, mechanism of nucleotide selection by DNA polymerases, role of mutator mutants in the adaptive evolution of bacteria and their resistance to antibiotics, first incipient (real-time) speciation of bacteria in the laboratory, first direct visualization, in real time, in living bacteria, at single cell level, of (i) the horizontal gene transfer, (ii) the chromosomal crossing over and (iii) all spontaneous mutations emerging in growing bacteria, the mechanism of the most efficient DNA repair system in the highly radiation-resistant bacterium Deinococcus radiodurans and the molecular basis of its robustness, are all textbook materials.
The PI has been a “scientific nomad” working for extended periods in Croatia, Belgium, France, USA and again Belgium before settling down in France in 1983. Trained in physical chemistry (4 semesters), physics (4 semesters) and higher mathematics (3 semesters) while studying undergraduate biology at the University of Zagreb, M.R. became the assistant to Professor Ivan Supek (a Copenhagen school physicist also holding PhD in philosophy and a co-founder of the Pugwash movement) even before graduation. At age 23 M.R. went to the University of Brussels, as the first pre-doctoral fellow of EMBO, to study radiobiology with Professor Maurice Errera and phage l genetics with Professor René Thomas, where he got his PhD degree at age 25. Moved for a year to Paris to study bacterial genetics with Dr. R. Devoret, then became a post-doctoral fellow with Matthew Meselson at Harvard in the fall of 1970, when he conceived the SOS repair hypothesis published only in 1973. Nominated associate professor at the University of Brussels at the age 28, moved to Brussels in 1973 heading the DNA Enzymology group for 10 years before moving to France to found the CNRS Mutagenesis Unit as the CNRS research director at the Institute Jacques Monod. Finally, nominated Professor of Medicine moved to the University R. Descartes-Paris 5 Medical School Necker in 1998 to head for 12 years the “Evolutionary and Medical Molecular Genetics” INSERM Unit 571 (now U1001). The professional and personal life of the PI was marked by the privilege of having spent considerable time with several giants of molecular biology (M. Meselson, M. Perutz, F. Jacob, S. Brenner, E. Witkin, F. Sanger, J. Watson, W. Gilbert, M. Ptashne, etc). The PI was the youngest EMBO member, youngest professor at the University of Brussels and is recipient of a dozen of awards. In the scholarly book “The century of the gene” (Harvard University Press, 2000) by Evelyn Keller Fox, this PI is the fifth most frequently cited scientist.
Nothing looks standard in PI’s career; it was always the search for new vistas, asking new questions, using a variety of experimental systems from bacteria to mice, and often creating new methods. Even the way his INSERM Unit was run is unorthodox: with his former PhD students Ivan Matic and François Taddei, the PI was running a large research unit called the TaMaRa lab (for Taddei, Matic, Radman) for an effective triumvirate. As the director, M.R. signed no more than 25% of his laboratory’s papers over the last ten years: only those with his personal projects, with no more than 3-4 pre- and post-doctoral collaborators. With Matic and Taddei, today leaders in modern microbiology, systems and synthetic biology and nano-biology, PI shares all material and intellectual resources resulting in what is today publication-wise the most productive laboratory in France (when normalized by scientist, or by euro).
M.R. has trained over 60 PhD students, a dozen of whom became professors and lab directors in major academic institutions in Europe, USA and Japan.
PI’s laboratory is truly interdisciplinary methodology-wise (genetics, biochemistry, enzymology, cell biology, diverse microscopy, microfluidics, bioinformatics and mathematical modelling) and organism-wise (bacteria, yeast, nematode, rotifers and mice).
PI’s special achievement and passion is the foundation of the Mediterranean Institute for Life Sciences in Split Croatia (www.medils.hr): a fully independent, private, non-profit international institute for “thinking the unthinkable” –that started three years ago.
Born April 30, 1944 in Split (Croatia). Citizen of Croatia and France. Languages spoken: Croatian, French, English, German and Italian.
Studies and Degrees: 1962-66:B. Sc. in experimental biology and physical chemistry, University ofZagreb, Yugoslavia. 1966-67: Graduate studies in molecular biology, same University. 1967-69: Graduate research in Department of Molecular Biology, Free University of Brussels, Belgium. 1969: Ph.D. from the Free University of Brussels, Belgium.
Positions held: 1965-67: Part-time research assistant to Professor Ivan Supek, Institute for Philosophy ofScience and Peace Research. Zagreb. Experimental work with Dr.M. Drakulic (Institute Ruder Boskovic Zagreb, Croatia). 1967-69: Pre-doctoral research fellow with Professors M. Errera and R.Thomas, Dept. of Molecular Biology, Free University of Brussels, Belgium. 1969-70: Post-doctoral research fellow with Professor R. Devoret, CNRS, Gif-sur-Yvette, France. 1970-73: Post-doctoral Research Fellow with Professor M. Meselson, Dept. of Biochemistry and Molecular Biology, Harvard University, Cambridge, Ma, U.S.A. 1972: Associate Professor of Molecular Genetics, Department of Molecular Biology, Free University of Brussels. 1973-83: Tenured Research Professor and head of the Laboratory of Enzymology of DNA (Same institution). 1983-98: Research Director of the French CNRS, Institute Jacques Monod (University Paris 7, Paris). 1988 / 90: Visiting Scientist, National Institutes of Environmental Health Sciences, N.I.H., Research Triangle Park, NC 27709, USA. 1998: Professor of Cell Biology, Medical School "Necker - Enfants Malades", Université Paris 5. 1999: Director, INSERM research unit U571“ Medical and evolutionary molecular genetics ”. 2004: Special Science Adviser to the Prime Minister of Croatia. 2008: Exceptional class Professor of Cell Biology at the R. Descartes-Paris-5 School of Medicine.
Research: Received over 80 research grants, 7 patents, 199 publications in the areas of DNA repair,replication, mutagenesis, genetic recombination, evolution of species, carcinogenesis and aging.
Citations: 3 discoveries present in most of molecular biology and genetics textbooks worldwide; about15.000 citations and up to 140.000 Google entries.
Funding: 240.000 euro per year from Inserm and a 2.5 million euro industrial grant to M. R. “with nostrings attached” derived from the patent on inter-species recombination (received in 2004). The Unit receives about 500.000 euro from grants allocated to I. Matic and F. Taddei.
A personal style: Although an outspoken critic of the establishment, known for his special personal style, this PI was always a careful and cautious research scientist who never had to correct a single sentence from his published papers. The exceeding cautiousness caused belated publication, in books, of his two most fundamental discoveries: SOS and mismatch repair (see below), such that he is not cited for them (which would count in tens of thousands of citations). This is particularly true for mismatch repair. The first experiment with reconstituted hemi-methylated phage l heteroduplex DNA was conceived and done by the PI in May of 1976 in M. Meselson’s laboratory that proved Meselson’s intuition correct: only methylated strands gave progeny. But the publication awaited MR’s isolation of mutS, mutL and mutH mismatch repair deficient mutants in 1979 to show that the 1976 result was due to a localised repair event rather than a DNA strand loss. The isolation of first mismatch repair mutants was published in PNAS, and the first experiment of transfection with reconstituted hemimethylated heteroduplex DNA in a congress book, both in 1980. Followed the mismatch repair specificity and mechanistic studies, along with the NMR structural studies of the in vivo studied mismatches. The conclusion was: the more frequent the replication error, the more fitting is the mismatched base within the helix and the better it is repaired.
The finding that the sterile crosses between Escherichia and Salmonella genera become fertile when the female cell is mismatch repair deficient was a world-wide boom, that was reinforced by later finding that the amount of two proteins, MutS and MutL, determines the gene flow between bacterial species: genetic barriers can be eliminated or generated depending on the amount of MutSL proteins. This fundamental work brought about construction of the most efficient “gene machine”: a l phage that can recombine cloned similar but sequence-diverged genes from any species and generate overnight a new family of millions of new mosaic genes per plate. This patented work brought 3 M USD of research money to the laboratory allowing acquisition of a powerful microscopic equipment that shifted our research capacity to the level of world’s top fluorescent microscopy of bacterial cells.
1. A list of the top 10 publication as senior author
A comment: M.R.'s publication record is by itself original to say the least. His most important conceptual discovery - the SOS response - was published in a conference proceeding (M. Radman "Phenomenology of an inducible mutagenic DNA repair: SOS repair hypothesis" in Molecular and environmental aspects of mutagenesis, Eds Prakash et al., Thomas Publ. 1974). The first experiment showing the existence of methyl-directed mismatch repair was also published in a conference proceeding (Radman, Wagner, Glickman and Meselson "DNA methylation, mismatch correctionand genetic stability" in Progress in Environmental Mutagenesis, Ed M. Alacevic, Elsevier Publ.1980). PI's by far best experimental paper, probably one of most sophisticated papers in molecular genetics accepted and published within 3 weeks (Jones, Wagner & Radman "Mismatch repair and recombination in E. coli" Cell (1987) 50: 621) was almost never quoted! But this paper that led PI to hypothesize the definition of the genetic barrier between closely related bacterial species (Rayssiguier, Thaler & Radman, Nature 342 (1989) 396), confirmed later in meiotic sterility experiments in yeast, got the world-wide scientific and public media acclamation.
I recognize that my own most productive period started when my former students I. Matic and F. Taddei rapidly became collaborating colleagues (cca from 1995); that period is in still blossoming.
In the below selected list of papers, I avoided some important papers where my colleagues' impact was not equalled by mine.
Average citations per paper: 61, 52
From 1996 to 2010 there is an uninterrupted citation between 300 and 400 times per year.
The list of top 10 publication in last 10 years (Average IF=21)
- Title: Oxidative stress resistance in Deinococcus radiodurance. Slade D, Radman M, MICROBIOLOGY MOL BIOL REV 75(1):133-191 (2011[FX1] )
- Title: RecA protein assures fidelity of DNA repair and genome stability in Deinococcus radiodurans. Repar J, Cvjetan S, Slade D, Radman M et al. DNA Repair (Amst.) 9(11) :1151-1161 (2010)
- Title : Unstructured hydrophilic sequences in prokaryotic proteomes correlate with dehydration tolerance and host association Krisko A, Smole Z, Debret G, Nikolic N, Radman M. J MOL BIOL 405(5):775-782 (2010)
- Title: Protein damage and death by radiation in Escherichia coli and Deinococcus radiodurans . Krisko A, Radman M, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107(32):14373-14377 (2010) Times Cited: 1 (0 self citation), IF=9,432
- Title: Seeing Mutations in Living Cells. Elez M, Murray AW, Bi LJ, et al. CURRENT BIOLOGY 20(16):1432-1437 (2010) Times Cited: 1(0 self citation), IF=10,992
- Title: Recombination and Replication in DNA Repair of Heavily Irradiated Deinococcus radiodurans Slade D, Lindner AB, Paul G, Radman M, CELL 136(6):1044-1055 2009 Times Cited: 28 (0 self citation), IF= 31,152
- Title: The lambda Red proteins promote efficient recombination between diverged sequences: Implications for bacteriophage genome mosaicism Martinsohn JT, Radman M, Petit MAS, PLOS GENETICS 4:5 Article Number: e1000065 (2008) Times Cited: 9 (0 self citation), IF=9,532
- Title: Direct visualization of horizontal gene transfer Babic A, Lindner AB, Vulic M, Stewart, E, Radman M, SCIENCE 319 ( 5869): 1533-1536 ( 2008) Times Cited:32 (0 self citation), IF=29.747
- Title: The frequency and structure of recombinant products is determined by the cellular level of MutL Elez M, Radman M, Matic I, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 104 (21): 8935-8940 (2007) Times Cited: 6 (2 self citations) IF=9,432
- Title: Reassembly of shattered chromosomes in Deinococcus radiodurans Zahradka K, Slade D, Bailone A, Sommer, S, Averbeck, D, Petranovic, M, Lindner, AB, Radman M, NATURE 443 (7111): 569-573 ( 2006) Times Cited: 102 (3 self citations) IF=34,480
- Title: Bacterial sex: Playing voyeurs 50 years later Kohiyama M, Hiraga S, Matic I, Radman M, SCIENCE 301(5634) 802-803 (2003) Times Cited: 9 (1 self citation), IF=29,747
- Title: Stress-induced mutagenesis in bacteria Bjedov I, Tenaillon O, Gerard B, Souza V, Denamur E, Radman M, Taddei F, Matic I, SCIENCE 300 (5624 ):1404-1409 (2003) Times Cited:161 (1 self citation), IF=29,747
- Title:Molecular biology - Specialized DNA polymerases, cellular survival, and the genesis of mutations Friedberg EC, Wagner R, Radman M, SCIENCE 296 (5573) :1627-1630( 2002) Times Cited: 246 (2 self citations), IF=29,747
- E.C. Friedberg “Correcting the Blueprint of Life: An historical account of the discovery of DNA repair mechanisms”, Cold Spring Harbor Laboratory Press, 1997 (two out of five chapters)
- M. Radman « Au dela de nos limites biologiques » (Beyond our biological limits), Le Plon, Paris, June 2011.
3. Granted patents
- French patent N° FR2948125 (A1) (21 janvier 2011) by: Z. Dermanovic, M. Radman, “Procédes d’Etablissement de Symbioses”.
- French patent N° FR2923491 (A1) (15 mai 2009) by: M. Radman, C. Rayssiguier, “Procede de Recombinaison in Vivo de Sequences d'ADN Presentant des Mesappariements de Bases »
- French patent N° PCT/FR2008/000318 (12 mars 2008) by: M. Radman, Ana Babic, Ariel B.Lindner “A method and system for monitoring horizontal gene transfer in living and fixed cells, and uses thereof
- International patent N° PCT/EP2006/005826 (10 mai 2006) by: M. Radman, ksenija Zahradka “Process of chromosomal engineering using a novel DNA repair system
- International patent N° EP 1 718 745 (26 fev 2004) by: A. Gomez-Rodriguez (ES); T. Galic(HER); M-A. Petit (FR); I. Matic (FR); M. Radman “Generation of recombinant genes in prokaryotic cells by using two extrachromosomal elements”
- International patent N° EP 1763 579 (6 juil. 2004) by: A. Luque (AR/FR); H. Strobel (DE/FR); J.T. Martinsohn (DE/FR); M-A. Petit (FR); M. Radman (FR/FR) “Generation of recombinant genes in bacteriophages”
- (6 Ter) International patent N° PCT/EP2002/1 4533 (19/12/2002) by: I. Matic & M. Radman“ Process for reversible functional inactivation of the mismatch repair system
- American Patent application US2002/0132259 (21/02/2001) by: R. Wagner & M. Radman “ Mutation detecting using MutS and RecA”
- International patent N° PCT/EP1995/002980 (26 Juil; 1995) by: H. P. Setratech Te Riele ; J. De Wind, ; H.M. Dekker-Vlaar, H ; M. Radman “Homologous recombination in mismatch repair inactivated eukaryotic cells"
- American Patent N° US patent 533 4522 (August 2, 1992) by: M. A. Resnick & M. Radman "System for isolating and producing new genes, gene products and DNA sequences"
- International patent N° PCT /FR 1989/000673 (12/07/1990) by: M. Radman & C. Rayssiguier"Procédé de recombinaison in vivo de séquences d’ADN partiellement homologues"
4. Invited presentations
Invitations: 198 international congresses, 44 keynote, plenary, introductory or closing lectures, andapprox. 500 seminars.
M.R. was invited speaker at both (New York and London-Cambridge) celebrations of the 50th anniversary of the DNA structure, and was selected for the jubileum’s press conference in the Royal Society (with Watson, Brenner, Jeffreys and Lord May) while 17 Nobel laureates were present. This appears as recognition, at the highest scientific level, of the impact of M.R.’s ideas and research on modern biology.
5. Organization of international conferences in the field of applicants
In the early stage of his career, the PI has organised five international schools and symposia. In last four years, he co-organized a dozen of summer schools and workshops in MedILS (Croatia), including two entitled “Surviving Death”.
With Francois Taddei as the leader, MR participated and supported financially from the laboratory resources the first European undergraduate then graduate school of interdisciplinary studies of life http://www.necker.fr/tamara/, interdisciplinary teaching & http://abraxa.snv.jussieu.fr/people/erocha/aivweb/
6. International prizes/Awards/academy memberships
Membership in four academies of sciences and arts, about 15 national and international awards and over 40 keynote, closing and introductory talks at international congresses also witness M.R.’s impact on molecular biology.
Honorary Awards: 1979:"Antoine Lacassagne" Grand Prix, Award of the French Ligue AgainstCancer (Ligue Nationale Française contre le Cancer) for the discovery of the mutagenic SOS system in bacteria. 1990: “Golden Eureka of Innovation”. 1991: FEBS International Lecturer. 1992: “Charles Leopold Meyer” Grand Prix of the French Academy of Science for the discovery of DNA error correction (mismatch repair). 1992: Medal of Honor: Society for the Encouragement of Progress. 1998: Medal "Spiridion Brusina" for the 100th anniversary of the Croatian Naturalists' Society. 1998: Grand Prix "Leopold Griffuel" of the Association pour la recherche sur le Cancer for the contributions to the field of DNA repair. 2000: Grand Prix "Richard Lounsbery" Joint Award of the French and United States national academies of science for the discovery of mismatch repair as a genetic barrier between related species. 2000: Science Award 2000 from the “U.S. Environmental Mutagen Society” for “far-reaching research contributions to understanding the profound consequences of mutation and recombination, in global genomic responses, DNA repair, cancer and evolution”. 2000: “Katzir Katchalsky Honorary Lecturer”, Weizmann Institute, Israel. 2002: Honorary Visiting Professor of Molecular Genetics, Faculties of Science & Medicine, Zagreb University, Croatia. 2003: Grand Prix INSERM; Speaker at the Celebration of the 50th anniversary of the discovery of DNA structure (Roy. Soc. & CSHL); 2004: Leonardo Award for creativity in scientific research. 2005: Linus Pauling Medal by the International League of Humanists as the “scientist humanist of the decade”. National Science Award of Croatia; 2009: Highest level state decoration by the President of Croatia S. Mesic. 2011: André Lwoff Prize of the Federation of European Microbiological Societies (FEMS).
Membership: EMBO member (1978), Croatian Academy of Sciences and Arts (1992), AcademiaEuropaea (1998), French “Académie des Sciences” (2002) and World Academy of Arts and Sciences (2005) and a number of professional societies and editorial boards in the past. Currently, member of the ERC panel LS4 (2008), Microsoft International Expert Group (2005), Board of the AXA Research Fund (2007) and UNESCO International Bioethics Committee (2005).
6. Memberships to editorial boards of international journals
Mutation Research (1980-1988)
DNA Repair (2001-2005)