- Email: [email protected]
The 2005 Benjamin Franklin medal in life sciences awarded to Elizabeth Blackburn
ARTICLE IN PRESS
Journal of the Franklin Institute 343 (2006) 257–262 www.elsevier.com/locate/jfranklin
The 2005 Benjamin Franklin medal in life sciences awarded to Elizabeth Blackburn Jane Azizkhan-Clifford Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA
Abstract The Franklin Institute awarded the 2005 Franklin medal in life sciences to Dr. Elizabeth Blackburn for her pioneering work on understanding how the cell preserves the ends of chromosomes, telomeres, while replicating its DNA. Dr. Blackburn identified the sequence of telomere DNA, and found very simple repeat sequences that are interchangeable among many eukaryotic organisms. Subsequently, she discovered telomerase, the enzyme that ensures telomere maintenance, and demonstrated that telomerase has both RNA and protein components, with the RNA serving as the template for the reverse transcriptase. The dynamic nature of telomerase is linked to the replicative potential of the cell. Dr. Blackburn’s work on telomeres has given new insights into aging and disease, including cancer. r 2006 The Franklin Institute. Published by Elsevier Ltd. All rights reserved.
1. Historical context Arguably one of the greatest discoveries in science was the discovery of the structure of DNA in 1953 [1]. Determination of the structure of DNA, for which James Watson, Francis Crick and Maurice Wilkins were awarded the Nobel prize in 1962, was the result of 25 years of research by numerous scientists armed with the realization that chromosomes were comprised of DNA and were replicated during cell division. Resolution of the structure of the nitrogenous bases and their relationship to one another revealed that each strand of DNA has a directional nature based upon the pairing and orientation of the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245 N. 15th Street, M.S. 497, Philadelphia PA 19102, USA. Tel.: 215 762 4446; fax: 215 762 4452. E-mail address: [email protected].
0016-0032/$30.00 r 2006 The Franklin Institute. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jfranklin.2006.03.007
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bases relative to the adjacent base—so-called base stacking, and that the two strands pair with one another in an anti-parallel fashion, i.e. in opposite directions relative to one another, forming what they called the ‘‘double helix’’. Armed with an understanding of what the DNA molecule looked like, an initial understanding of the mechanism by which a cell replicates its DNA to produce an identical daughter cell began to emerge not long thereafter. DNA replication proved to be semi-conservative, that is, each newly synthesized strand is a complete copy of one of the parent strands and each new molecule has one ‘‘old’’ and one ‘‘new’’ strand of DNA [2]. Since DNA replication can only occur in one direction, duplication of the two strands must effectively proceed in opposite directions from a single point which is called the origin of replication. The two complimentary DNA strands progressively unwind and are independently duplicated to produce an identical daughter cell. DNA replication relies on small RNA molecules that serve to prime the synthesis by annealing to the DNA being replicated. For one of the strands, the so-called leading strand, a single primer is sufficient to allow the enzyme (DNA polymerase) to continuously copy the template strand as it moves toward the point, the replication fork, where the template strands are incrementally separating from one another. Replication of the so-called lagging strand is complicated by the fact that the DNA unwinds over a relatively short distance; to comply with the directional restriction, it must be primed from the replication fork. Therefore multiple primers are required and multiple short segments of DNA are made, which are called Okazaki fragments after their discoverer [described in a series of papers published between 1967 and 1975 [3], for review)]. The Okazaki fragments are ligated together to form a continuous duplicated strand. Because chromosomes are linear, the DNA on the lagging strand between the last RNA primer and the end of the chromosome cannot be replicated as there is no DNA beyond the end to which the next RNA primer can anneal, thus this gap cannot be filled in (this is referred to as the ‘‘end replication problem’’). The end of the chromosome is thereby shortened with each round of replication. The foundations for Blackburn’s discoveries were established by the work of Herman Muller with drosophila and Barbara McClintock on maize, both of whom recognized the uniqueness of the chromosome end. Muller discovered that chromosome breaks resulting from irradiation were repaired whereas chromosome ends were not joined, suggesting that there must be a special function to the terminal gene to seal the end of the chromosome; he coined the term ‘telomere’ from the Greek word meaning ‘end part’ [4]. McClintock discovered the chromosomal basis of heredity by demonstrating a direct relation between chromosomal crossing over and genetic recombination, as well as breakage-fusion-bridge cycle. Based on her studies, McClintock hypothesized the existence of a special structure at the chromosome tip [5]. Telomeres keep the ends of the various chromosomes in the cell from becoming entangled and sticking to each other and assist in the pairing of homologous chromosomes. They also protect the chromosome ends from being detected as double strand breaks which would be subjected to recombination producing genomic instability. Taken together with the discovery of the limited replicative potential of mammalian cells, the notion emerged that chromosome ends must be comprised of unique sequence that is not recognized as a double strand break and is not degraded. The telomere protects the information-containing genes, so that the loss of some telomeric nucleotide sequences at each round of DNA replication does not result in the loss of genetic information.
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2. Work of Dr. Elizabeth Blackburn Dr. Blackburn earned her B.Sc. (1970) and M.Sc. (1972) degrees from the University of Melbourne in Australia, and her Ph.D. (1975) from the University of Cambridge in England. She did her postdoctoral work in Molecular and Cellular Biology from 1975 to 1977 at Yale. Her interest in telomeres began during her time as a postdoctoral fellow with Dr. Joseph Gall at Yale University, where she determined the sequence of chromosome ends, known as telomeres. She began her independent academic career at the University of California at Berkely in 1978 and in 1990, she moved to the University of California at San Francisco where she served as Chair of the Department of Biochemistry and Biophysics from 1993–1999 and is currently the Morris Herzstein Professor of Biochemistry and Physiology in the Department of Biochemistry and Biophysics. Working with Tetrahymena, a ciliated protozoan, and knowing that a small section of telomeres was not copied as cells divided and chromosomes were replicated, Dr. Blackburn, while a post-doctoral fellow in Dr. Joseph Gall’s laboratory at Yale, became interested in why this did not result in significantly shorter telomeres with each division, i.e. maintenance of telomere length could not be reconciled with the end replication problem. One of the first steps in determining the basis of telomere maintenance was their cloning and sequencing. The sequence of the telomere was found to be a simple 6 base pair sequence that is repeated as many as 2000 times. In collaboration with Dr. Jack Szostak, a pre-eminent biophysicist at Harvard University, Dr. Blackburn found that telomeres are fundamentally the same in all eukaryotic organisms; Tetrahymena telomeres could substitute for telomeres in the distantly related organism S. cerevisiae, a yeast. Dr. Blackburn recognized the importance of this experiment—it suggested that each organism would contain an enzyme that would manufacture the repeated DNA sequence of telomeres and provide a solution to the ‘‘self-renewal’’ properties of telomeres. With her graduate student, Carol Greider, now a professor at Johns Hopkins University, she successfully found such an ‘enzyme’. The search was confounded by the fact that the enzyme was present in very low quantity. They isolated the enzyme from Tetrahymena that were synchronized at a point in the cell cycle where expression of such an enzyme would be the highest, and they used synthetic DNA comprised of the telomere sequence to isolate the enzyme by DNA affinity. In a landmark paper published in 1985, Greider and Blackburn [6] demonstrated that there was an enzyme that added TTGGGG to synthetic substrates in vitro and called this enzyme telomerase. In subsequent papers, they demonstrated that telomerase was comprised of both protein and RNA and that the RNA provides a template to ensure that the enzyme adds the correct repeat sequence. In 1990, Blackburn and colleagues proved this by mutating the template portion of the RNA and demonstrating that the repeat sequence of the telomere was changed [7]. Every time a cell divides, telomeres, which act like the plastic tips on the ends of shoelaces, get shorter. In the natural aging process, the telomeres eventually get so short that cells can no longer divide, and they die. Telomerase levels are very low in normal cells and therefore telomeres become shorter with successive DNA replication. In 1998, Bodnar et al. [8] demonstrated that the replication limits of cells could be overcome by transfecting somatic cells with telomerase. Cells regained replicative capacity, telomeres were not shortened, and cells became immortalized; however, they did not become cancer cells. The discovery of telomerase allowed demonstration that the Hayflick [9] limit was related to the shortening of the telomere and that telomerase was related to cell aging. The ability to
ARTICLE IN PRESS 260
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immortalize human cells and retain normal behavior has tremendous implications in drug development and gene therapy. It should facilitate development of cellular models of human disease with the potential to produce unlimited quantities of normal human cells of virtually any cell type. The implications for transplantation and perhaps gene therapy are profound; an individual’s cells immortalized by telomerase and corrected for a genetic defect could be used as cell-based therapies for specific genetic disorders, such as cystic fibrosis or muscular dystrophy. Telomerase activity is regulated and is differentially expressed in different cell types. Telomerase activity of stem cells or self-renewing tissues, like bone marrow, small intestine and lymphocytes, is increased when these cells are induced to proliferate. Telomerase activity is also high in germline (reproductive) cells, wherein telomere length is maintained. Because cancer cells divide rapidly, their telomeres should get shorter more quickly than normal cells; however, telomerase is expressed at a higher level in tumor cells and tumor cells show no loss of telomere length with cell division which may in part explain their escape from senescence. Telomerase levels may prove to be a useful prognostic indicator of the metastatic phenotype. It is not known whether telomerase activation is just a marker for cancer cells or involved in causing it. In either case, agents with anti-telomerase activity are being developed and tested for treatment of primary malignancies, as well as for use in combination with other therapies or for the prevention of metastases. While many other labs around the world contributed greatly to the current understanding of telomeres and the duplication of chromosome ends, Elizabeth Blackburn is responsible for having established a field of scientific investigation. In 1987, 2 years after the initial report, there were 5 papers published on telomerase, 3 of which were from Dr. Blackburn’s laboratory; in 2004, there were 925 papers published, many of which were from the laboratories of scientists who had trained with Dr. Blackburn. Robert Weinberg (MIT) in supporting Dr. Blackburn’s nomination for the Franklin medal stated, ‘‘It is rare that a sub-field of modern biological research can trace its roots directly and unambiguously to the work of a single individual.’’ ‘‘Her seminal discovery of telomerase ranks among the watershed events in recent biology and has generated an entire field.’’ (Steve Elledge, Harvard Medical School). Nobel laureate, Tom Czech (President, Howard Hughes Medical Institute) summarized his comments saying, ‘‘I think that Liz will win the Nobel Prize in Physiology and Medicine for her discovery of telomerase.’’ The influence of the initial discovery has been far reaching and Dr. Blackburn continues to be a leader in the field. Recent work from Dr. Blackburn’s laboratory has demonstrated that the telomere is dynamic and that the telomere length actually informs the cell of its growth stage or replicative potential. Dr. Blackburn has been honored by many prestigious awards. These include the Eli Lilly Research Award for Microbiology and Immunology (1988), the National Academy of Science Award in Molecular Biology (1990), and an Honorary Doctorate of Science from Yale University (1991). She was a Harvey Society Lecturer at the Harvey Society in New York (1990), and the recipient of the UCSF Women’s Faculty Association Award (1995). Most recently, she was awarded the Australia Prize (1998), the Harvey Prize (1999), the Keio Prize (1999), American Association for Cancer Research-G.H.A. Clowes Memorial Award (2000), American Cancer Society Medal of Honor (2000), AACRPezcoller Foundation International Award for Cancer Research (2001), General Motors Cancer Research Foundation Alfred P. Sloan Award (2001), E.B.Wilson Award of the American Society for Cell Biology (2001), 26th Annual Bristol-Myers Squibb Award for
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Distinguished Achievement in Cancer Research (2003), and the Dr. A.H. Heineken Prize for Medicine (2004). She was recently selected for receipt of 2005 Landon—AACR Prize for Cancer Research from the American Association for Cancer Research. She was named California Scientist of the Year in 1999, was elected President of the American Society for Cell Biology for the year 1998, and served as a Board member of the Genetics Society of America (2000–2002). Dr. Blackburn is an elected Fellow of the American Academy of Arts and Sciences (1991), the Royal Society of London (1992), the American Academy of Microbiology (1993), and the American Association for the Advancement of Science (2000). She was elected Foreign Associate of the National Academy of Sciences in 1993, and was elected as a Member of the Institute of Medicine in 2000. Dr. Blackburn served as a member of The President’s Council on Bioethics. 3. Legacy of 2005 Franklin medal awarded to Elizabeth Blackburn, Ph.D. The foundation and the tools for Dr. Blackburn’s discoveries can be found in the discoveries of previous laureates of the Franklin Medal in Life Sciences or the Bower Award. In 1920, B.H. Hite received the Franklin medal for developing high pressure sterilization which is essential for sterilization of media for growth of microorganisms and cells and in 1925, Ross Harrison received the Franklin medal for developing methods to grow cells in tissue culture. Marshall Nirenberg was awarded a Franklin Medal in 1968 for deciphering the genetic code, an essential discovery for Dr. Blackburn’s work. In 1978, Mahlon Hagland was awarded the Franklin medal for his role in the discovery of the mechanisms of protein synthesis relative to information coded in DNA and RNA, again, essential to Dr. Blackburn’s work. Monoclonal antibodies, which are used extensively in Dr. Blackburn’s research, were discovered by Cesar Milstein who was awarded the Franklin medal in 1982. In 1994 Marvin Caruthers received the Franklin Medal for his contributions to the synthesis of oligonucleotides—a breakthrough that was essential to Dr. Blackburn’s experiments. In 1997, Ralph Brinster received the Bower Award for groundbreaking work in developing technologies for transgenic animals. The 2000 Bower was awarded to Alexander Rich for elucidating the three dimensional structure of RNA and DNA which was essential to understanding telomeres. These are a few of the most notable previous laureates whose work has profoundly impacted on the discoveries that led to Dr. Elizabeth Blackburn’s receipt of the 2005 Franklin medal in the Life Sciences. References [1] J.D. Watson, F.H.C. Crick, Molecular Structure of Nucleic Acids—A Structure for Deoxyribose Nucleic Acid, Nature 171 (1953) 737–738. [2] M. Meselson, F.W. Stahl, The replication of DNA, Cold Spring Harbor Symp. Quant. Biol. 23 (1958) 9–12. [3] T. Ogawa, T. Okazaki, Discontinuous DNA replication, Annu. Rev. Biochem. 49 (1980) 421–457. [4] H.J. Muller, The remaking of chromosomes, Collecting Net 8 (1938) 182–198. [5] B. McClintock, The fusion of broken chromosomes ends of sister half-chromatids following chromatid breakage at meiotic anaphases, Missouri Agricultural Experiment Station Research Bulletin 290 (1938) 1–48. In: J.A. Moore (Ed.), The Discovery and Characterization of Transposable Elements, Garland Publishing, New York, 1987. [6] C.W. Greider, E.H. Blackburn, Identification of a specific telomere terminal transferase activity in Tetrahymena extracts, Cell 43 (2, P and t 1) (1985) 405–413. [7] D. Shippen-Lentz, E.H. Blackburn, Functional evidence for an RNA template in telomerase, Science 247 (1990) 546–552.
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[8] A.G. Bodnar, M. Ouellette, M. Frolkis, S.E. Holt, C.P. Chiu, G.B. Morin, C.B. Harley, J.W. Shay, S. Lichtsteiner, W.E. Wright, Extension of life-span by introduction of telomerase into normal human cells, Science 729 (1998) 349–352. [9] L. Hayflick, P.S. Morehead, The serial cultivation of human diploid cell strains, Exp. Cell Res. 25 (1961) 585–621.
Journal of the Franklin Institute 343 (2006) 257–262 www.elsevier.com/locate/jfranklin
The 2005 Benjamin Franklin medal in life sciences awarded to Elizabeth Blackburn Jane Azizkhan-Clifford Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA
Abstract The Franklin Institute awarded the 2005 Franklin medal in life sciences to Dr. Elizabeth Blackburn for her pioneering work on understanding how the cell preserves the ends of chromosomes, telomeres, while replicating its DNA. Dr. Blackburn identified the sequence of telomere DNA, and found very simple repeat sequences that are interchangeable among many eukaryotic organisms. Subsequently, she discovered telomerase, the enzyme that ensures telomere maintenance, and demonstrated that telomerase has both RNA and protein components, with the RNA serving as the template for the reverse transcriptase. The dynamic nature of telomerase is linked to the replicative potential of the cell. Dr. Blackburn’s work on telomeres has given new insights into aging and disease, including cancer. r 2006 The Franklin Institute. Published by Elsevier Ltd. All rights reserved.
1. Historical context Arguably one of the greatest discoveries in science was the discovery of the structure of DNA in 1953 [1]. Determination of the structure of DNA, for which James Watson, Francis Crick and Maurice Wilkins were awarded the Nobel prize in 1962, was the result of 25 years of research by numerous scientists armed with the realization that chromosomes were comprised of DNA and were replicated during cell division. Resolution of the structure of the nitrogenous bases and their relationship to one another revealed that each strand of DNA has a directional nature based upon the pairing and orientation of the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245 N. 15th Street, M.S. 497, Philadelphia PA 19102, USA. Tel.: 215 762 4446; fax: 215 762 4452. E-mail address: [email protected].
0016-0032/$30.00 r 2006 The Franklin Institute. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jfranklin.2006.03.007
ARTICLE IN PRESS 258
J. Azizkhan-Clifford / Journal of the Franklin Institute 343 (2006) 257–262
bases relative to the adjacent base—so-called base stacking, and that the two strands pair with one another in an anti-parallel fashion, i.e. in opposite directions relative to one another, forming what they called the ‘‘double helix’’. Armed with an understanding of what the DNA molecule looked like, an initial understanding of the mechanism by which a cell replicates its DNA to produce an identical daughter cell began to emerge not long thereafter. DNA replication proved to be semi-conservative, that is, each newly synthesized strand is a complete copy of one of the parent strands and each new molecule has one ‘‘old’’ and one ‘‘new’’ strand of DNA [2]. Since DNA replication can only occur in one direction, duplication of the two strands must effectively proceed in opposite directions from a single point which is called the origin of replication. The two complimentary DNA strands progressively unwind and are independently duplicated to produce an identical daughter cell. DNA replication relies on small RNA molecules that serve to prime the synthesis by annealing to the DNA being replicated. For one of the strands, the so-called leading strand, a single primer is sufficient to allow the enzyme (DNA polymerase) to continuously copy the template strand as it moves toward the point, the replication fork, where the template strands are incrementally separating from one another. Replication of the so-called lagging strand is complicated by the fact that the DNA unwinds over a relatively short distance; to comply with the directional restriction, it must be primed from the replication fork. Therefore multiple primers are required and multiple short segments of DNA are made, which are called Okazaki fragments after their discoverer [described in a series of papers published between 1967 and 1975 [3], for review)]. The Okazaki fragments are ligated together to form a continuous duplicated strand. Because chromosomes are linear, the DNA on the lagging strand between the last RNA primer and the end of the chromosome cannot be replicated as there is no DNA beyond the end to which the next RNA primer can anneal, thus this gap cannot be filled in (this is referred to as the ‘‘end replication problem’’). The end of the chromosome is thereby shortened with each round of replication. The foundations for Blackburn’s discoveries were established by the work of Herman Muller with drosophila and Barbara McClintock on maize, both of whom recognized the uniqueness of the chromosome end. Muller discovered that chromosome breaks resulting from irradiation were repaired whereas chromosome ends were not joined, suggesting that there must be a special function to the terminal gene to seal the end of the chromosome; he coined the term ‘telomere’ from the Greek word meaning ‘end part’ [4]. McClintock discovered the chromosomal basis of heredity by demonstrating a direct relation between chromosomal crossing over and genetic recombination, as well as breakage-fusion-bridge cycle. Based on her studies, McClintock hypothesized the existence of a special structure at the chromosome tip [5]. Telomeres keep the ends of the various chromosomes in the cell from becoming entangled and sticking to each other and assist in the pairing of homologous chromosomes. They also protect the chromosome ends from being detected as double strand breaks which would be subjected to recombination producing genomic instability. Taken together with the discovery of the limited replicative potential of mammalian cells, the notion emerged that chromosome ends must be comprised of unique sequence that is not recognized as a double strand break and is not degraded. The telomere protects the information-containing genes, so that the loss of some telomeric nucleotide sequences at each round of DNA replication does not result in the loss of genetic information.
ARTICLE IN PRESS J. Azizkhan-Clifford / Journal of the Franklin Institute 343 (2006) 257–262
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2. Work of Dr. Elizabeth Blackburn Dr. Blackburn earned her B.Sc. (1970) and M.Sc. (1972) degrees from the University of Melbourne in Australia, and her Ph.D. (1975) from the University of Cambridge in England. She did her postdoctoral work in Molecular and Cellular Biology from 1975 to 1977 at Yale. Her interest in telomeres began during her time as a postdoctoral fellow with Dr. Joseph Gall at Yale University, where she determined the sequence of chromosome ends, known as telomeres. She began her independent academic career at the University of California at Berkely in 1978 and in 1990, she moved to the University of California at San Francisco where she served as Chair of the Department of Biochemistry and Biophysics from 1993–1999 and is currently the Morris Herzstein Professor of Biochemistry and Physiology in the Department of Biochemistry and Biophysics. Working with Tetrahymena, a ciliated protozoan, and knowing that a small section of telomeres was not copied as cells divided and chromosomes were replicated, Dr. Blackburn, while a post-doctoral fellow in Dr. Joseph Gall’s laboratory at Yale, became interested in why this did not result in significantly shorter telomeres with each division, i.e. maintenance of telomere length could not be reconciled with the end replication problem. One of the first steps in determining the basis of telomere maintenance was their cloning and sequencing. The sequence of the telomere was found to be a simple 6 base pair sequence that is repeated as many as 2000 times. In collaboration with Dr. Jack Szostak, a pre-eminent biophysicist at Harvard University, Dr. Blackburn found that telomeres are fundamentally the same in all eukaryotic organisms; Tetrahymena telomeres could substitute for telomeres in the distantly related organism S. cerevisiae, a yeast. Dr. Blackburn recognized the importance of this experiment—it suggested that each organism would contain an enzyme that would manufacture the repeated DNA sequence of telomeres and provide a solution to the ‘‘self-renewal’’ properties of telomeres. With her graduate student, Carol Greider, now a professor at Johns Hopkins University, she successfully found such an ‘enzyme’. The search was confounded by the fact that the enzyme was present in very low quantity. They isolated the enzyme from Tetrahymena that were synchronized at a point in the cell cycle where expression of such an enzyme would be the highest, and they used synthetic DNA comprised of the telomere sequence to isolate the enzyme by DNA affinity. In a landmark paper published in 1985, Greider and Blackburn [6] demonstrated that there was an enzyme that added TTGGGG to synthetic substrates in vitro and called this enzyme telomerase. In subsequent papers, they demonstrated that telomerase was comprised of both protein and RNA and that the RNA provides a template to ensure that the enzyme adds the correct repeat sequence. In 1990, Blackburn and colleagues proved this by mutating the template portion of the RNA and demonstrating that the repeat sequence of the telomere was changed [7]. Every time a cell divides, telomeres, which act like the plastic tips on the ends of shoelaces, get shorter. In the natural aging process, the telomeres eventually get so short that cells can no longer divide, and they die. Telomerase levels are very low in normal cells and therefore telomeres become shorter with successive DNA replication. In 1998, Bodnar et al. [8] demonstrated that the replication limits of cells could be overcome by transfecting somatic cells with telomerase. Cells regained replicative capacity, telomeres were not shortened, and cells became immortalized; however, they did not become cancer cells. The discovery of telomerase allowed demonstration that the Hayflick [9] limit was related to the shortening of the telomere and that telomerase was related to cell aging. The ability to
ARTICLE IN PRESS 260
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immortalize human cells and retain normal behavior has tremendous implications in drug development and gene therapy. It should facilitate development of cellular models of human disease with the potential to produce unlimited quantities of normal human cells of virtually any cell type. The implications for transplantation and perhaps gene therapy are profound; an individual’s cells immortalized by telomerase and corrected for a genetic defect could be used as cell-based therapies for specific genetic disorders, such as cystic fibrosis or muscular dystrophy. Telomerase activity is regulated and is differentially expressed in different cell types. Telomerase activity of stem cells or self-renewing tissues, like bone marrow, small intestine and lymphocytes, is increased when these cells are induced to proliferate. Telomerase activity is also high in germline (reproductive) cells, wherein telomere length is maintained. Because cancer cells divide rapidly, their telomeres should get shorter more quickly than normal cells; however, telomerase is expressed at a higher level in tumor cells and tumor cells show no loss of telomere length with cell division which may in part explain their escape from senescence. Telomerase levels may prove to be a useful prognostic indicator of the metastatic phenotype. It is not known whether telomerase activation is just a marker for cancer cells or involved in causing it. In either case, agents with anti-telomerase activity are being developed and tested for treatment of primary malignancies, as well as for use in combination with other therapies or for the prevention of metastases. While many other labs around the world contributed greatly to the current understanding of telomeres and the duplication of chromosome ends, Elizabeth Blackburn is responsible for having established a field of scientific investigation. In 1987, 2 years after the initial report, there were 5 papers published on telomerase, 3 of which were from Dr. Blackburn’s laboratory; in 2004, there were 925 papers published, many of which were from the laboratories of scientists who had trained with Dr. Blackburn. Robert Weinberg (MIT) in supporting Dr. Blackburn’s nomination for the Franklin medal stated, ‘‘It is rare that a sub-field of modern biological research can trace its roots directly and unambiguously to the work of a single individual.’’ ‘‘Her seminal discovery of telomerase ranks among the watershed events in recent biology and has generated an entire field.’’ (Steve Elledge, Harvard Medical School). Nobel laureate, Tom Czech (President, Howard Hughes Medical Institute) summarized his comments saying, ‘‘I think that Liz will win the Nobel Prize in Physiology and Medicine for her discovery of telomerase.’’ The influence of the initial discovery has been far reaching and Dr. Blackburn continues to be a leader in the field. Recent work from Dr. Blackburn’s laboratory has demonstrated that the telomere is dynamic and that the telomere length actually informs the cell of its growth stage or replicative potential. Dr. Blackburn has been honored by many prestigious awards. These include the Eli Lilly Research Award for Microbiology and Immunology (1988), the National Academy of Science Award in Molecular Biology (1990), and an Honorary Doctorate of Science from Yale University (1991). She was a Harvey Society Lecturer at the Harvey Society in New York (1990), and the recipient of the UCSF Women’s Faculty Association Award (1995). Most recently, she was awarded the Australia Prize (1998), the Harvey Prize (1999), the Keio Prize (1999), American Association for Cancer Research-G.H.A. Clowes Memorial Award (2000), American Cancer Society Medal of Honor (2000), AACRPezcoller Foundation International Award for Cancer Research (2001), General Motors Cancer Research Foundation Alfred P. Sloan Award (2001), E.B.Wilson Award of the American Society for Cell Biology (2001), 26th Annual Bristol-Myers Squibb Award for
ARTICLE IN PRESS J. Azizkhan-Clifford / Journal of the Franklin Institute 343 (2006) 257–262
261
Distinguished Achievement in Cancer Research (2003), and the Dr. A.H. Heineken Prize for Medicine (2004). She was recently selected for receipt of 2005 Landon—AACR Prize for Cancer Research from the American Association for Cancer Research. She was named California Scientist of the Year in 1999, was elected President of the American Society for Cell Biology for the year 1998, and served as a Board member of the Genetics Society of America (2000–2002). Dr. Blackburn is an elected Fellow of the American Academy of Arts and Sciences (1991), the Royal Society of London (1992), the American Academy of Microbiology (1993), and the American Association for the Advancement of Science (2000). She was elected Foreign Associate of the National Academy of Sciences in 1993, and was elected as a Member of the Institute of Medicine in 2000. Dr. Blackburn served as a member of The President’s Council on Bioethics. 3. Legacy of 2005 Franklin medal awarded to Elizabeth Blackburn, Ph.D. The foundation and the tools for Dr. Blackburn’s discoveries can be found in the discoveries of previous laureates of the Franklin Medal in Life Sciences or the Bower Award. In 1920, B.H. Hite received the Franklin medal for developing high pressure sterilization which is essential for sterilization of media for growth of microorganisms and cells and in 1925, Ross Harrison received the Franklin medal for developing methods to grow cells in tissue culture. Marshall Nirenberg was awarded a Franklin Medal in 1968 for deciphering the genetic code, an essential discovery for Dr. Blackburn’s work. In 1978, Mahlon Hagland was awarded the Franklin medal for his role in the discovery of the mechanisms of protein synthesis relative to information coded in DNA and RNA, again, essential to Dr. Blackburn’s work. Monoclonal antibodies, which are used extensively in Dr. Blackburn’s research, were discovered by Cesar Milstein who was awarded the Franklin medal in 1982. In 1994 Marvin Caruthers received the Franklin Medal for his contributions to the synthesis of oligonucleotides—a breakthrough that was essential to Dr. Blackburn’s experiments. In 1997, Ralph Brinster received the Bower Award for groundbreaking work in developing technologies for transgenic animals. The 2000 Bower was awarded to Alexander Rich for elucidating the three dimensional structure of RNA and DNA which was essential to understanding telomeres. These are a few of the most notable previous laureates whose work has profoundly impacted on the discoveries that led to Dr. Elizabeth Blackburn’s receipt of the 2005 Franklin medal in the Life Sciences. References [1] J.D. Watson, F.H.C. Crick, Molecular Structure of Nucleic Acids—A Structure for Deoxyribose Nucleic Acid, Nature 171 (1953) 737–738. [2] M. Meselson, F.W. Stahl, The replication of DNA, Cold Spring Harbor Symp. Quant. Biol. 23 (1958) 9–12. [3] T. Ogawa, T. Okazaki, Discontinuous DNA replication, Annu. Rev. Biochem. 49 (1980) 421–457. [4] H.J. Muller, The remaking of chromosomes, Collecting Net 8 (1938) 182–198. [5] B. McClintock, The fusion of broken chromosomes ends of sister half-chromatids following chromatid breakage at meiotic anaphases, Missouri Agricultural Experiment Station Research Bulletin 290 (1938) 1–48. In: J.A. Moore (Ed.), The Discovery and Characterization of Transposable Elements, Garland Publishing, New York, 1987. [6] C.W. Greider, E.H. Blackburn, Identification of a specific telomere terminal transferase activity in Tetrahymena extracts, Cell 43 (2, P and t 1) (1985) 405–413. [7] D. Shippen-Lentz, E.H. Blackburn, Functional evidence for an RNA template in telomerase, Science 247 (1990) 546–552.
ARTICLE IN PRESS 262
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[8] A.G. Bodnar, M. Ouellette, M. Frolkis, S.E. Holt, C.P. Chiu, G.B. Morin, C.B. Harley, J.W. Shay, S. Lichtsteiner, W.E. Wright, Extension of life-span by introduction of telomerase into normal human cells, Science 729 (1998) 349–352. [9] L. Hayflick, P.S. Morehead, The serial cultivation of human diploid cell strains, Exp. Cell Res. 25 (1961) 585–621.