Conversations with Laureates
Born on November 19, 1934 in Washington, D.C.
Education
1956: Graduates Cum Laude from Harvard College
1960: Graduates from Harvard Medical School
Brief Chronology of Employment
1962: Becomes a research associate at the NIH
1963: Joins the laboratory of Marshall Nirenberg at NIH
1972: Becomes chief of the laboratory of molecular genetics at NIH
1980: Returns to Harvard to head the new genetics department and becomes the John Emory Andrus Professor of Genetics at Harvard Medical School.
1986 – 2004: Becomes Senior Investigator at Howard Hughes Medical Institute
Important Places
National Institutes of Health (NIH)
Leder joined Marshall Nirenberg's lab at NIH in 1962, where they devised the triplet binding assay, a technique that significantly accelerated the process of elucidating the genetic code.
Harvard Medical School
Leder graduated from Harvard College and Harvard Medical School, where he later returned and is now John Emory Andrus Professor of Genetics.
Howard Hughes Medical Institute (HHMI)
The Howard Hughes Medical Institute is a nonprofit medical research organization that employs hundreds of leading biomedical scientists working at the forefront of their fields. In addition, through its grants program and other activities, HHMI is helping to enhance science education at all levels and maintain the vigor of biomedical science worldwide.
Important Occurrences
1963: Leder and the Genetic Code
"The way Marshall [Nirenberg] engaged the problem, and his enthusiasm and patience for naive people like myself, was something that just excited and attracted me." — Phil Leder
While still a young intern at the University of Minnesota Hospital, Phil Leder applied for a research position at the National Institutes of Health (NIH). This fateful move introduced him to Marshall Nirenberg and his work on deciphering the genetic code, and set the stage for Leder's own illustrious research career.
"To have a chance to work for the fellow who had been involved in that experiment, and whose work would be certainly one of the main initiatives in seeking to solve the problem of the genetic code, was an exciting prospect." — Phil Leder
Just months before, Nirenberg had stunned the scientific community with his discovery of the first chemical "code word" in the translation of biological information from messenger RNA to protein—namely, that a string of the nucleotide uridylic acid (UUU's) coded for the amino acid, phenylalanine. Though a great scientific breakthrough, many questions remained. Did the sequence of nucleotides matter? If so, what sequence coded for which amino acid?
To help answer these questions, Leder, working as a postdoc in Nirenberg's NIH lab, developed the "triplet binding assay," a technique that significantly accelerated the process of elucidating the genetic code, and for which Nirenberg received the 1968 Nobel Prize in Medicine and Physiology. The method involved radioactively labeling one amino acid at a time and filtering the mixture to capture and identify the bound molecules. Nirenberg and Leder announced the development of the triplet binding assay at the Sixth International Congress of Biochemistry held in New York City.
"They had established a quick and reliable experimental approach for determining base sequences of the sixty-four codons, one at a time." — Lily Kay, in Who Wrote the Book of Life?, Stanford University Press, 2000
1978: The Genetic Basis of Antibody Diversity
"When it was solved—and lots of people were involved in its solution—it turned out to be just a marvelously beautiful solution that nature had devised for producing literally tens of thousands, if not millions of different antibodies from a genome." — Phil Leder
While working on the genetic code as a postdoc in the 1960s, Phil Leder's fascination with another biological mystery was taking root. As an intern at the University of Minnesota, he had encountered a patient suffering from macroglobulinemia of Waldenström—a rare, pre-malignant disease characterized by an excess production of a certain type of antibody. Leder resolved to explore the enigma of antibody formation and with completion of his postdoctoral work, he set up his own lab at NIH devoted to the study of immunology.
At the time, no one knew how the body managed to respond to the vast number of potential antigens, or "foreign invaders" it encountered in a lifetime. What mechanism could generate such tremendous diversity in antibody production, triggered by a seemingly countless number of viruses, bacteria, and allergens?
Phil Leder's pioneering research in molecular genetics furthered the understanding that genetic re-shuffling—a sort of mix and match of gene components—was responsible for the great variety and specificity of immune responses. Although the 1987 Nobel Prize in Physiology or Medicine was awarded solely to Susumu Tonegawa for the "discovery of the genetic principle for generation of antibody diversity," Leder is recognized as having made major contributions toward this achievement.
1982: OncoMouse©—A Model for Studying Cancer
"The field that I thought would profit most by the application of recombinant DNA technology…would be the cancer field. I turned my attention to that as not only a fascinating problem, but a problem of enormous clinical importance, and importance in terms of doing something for the public good." — Phil Leder
In the 1980s, Dr. Leder began to focus on recombinant DNA technology and its application in the field of cancer research. Along with colleague Tim Stewart, Leder isolated a gene known as C-myc, which plays a role in the development of certain types of cancer. By modifying the gene's regulatory mechanism and injecting the gene into a mouse embryo, they created the oncomouse, a mouse with a tendency to develop mammary tumors. Scientists now had a model for studying cancer in a living organism.
1988: DuPont Invests in Basic Research
"Many professors in the period from the late nineteenth century through World War II had contended that university science should be unadulterated by commercial considerations....Yet, it is evident that taking patents on the results of faculty research is not new in the annals of American academia." — Daniel Kevles, Caltech Professor of Humanities, at a 1993 NAS workshop, "Sharing Laboratory Resources: Genetically Altered Mice."
Dr. Leder knows the arguments well. His work in developing a genetically altered mouse, the oncomouse, as a model for studying cancer was funded by a grant from DuPont. And in 1988, the first patent for an animal was awarded to Harvard for Leder's creation of the oncomouse, with DuPont gaining exclusive rights to its use, generating controversy in the U.S. and abroad.
Like it or not, partnerships between commercial funding sources and academic research are a growing trend. For-profit companies investing in promising research efforts hope to reap financial reward from the discoveries—and patents—that may result.
"There are two ways of looking at the industrial relationship that an academic scholar can involve him- or herself in. One of those is to compensate for sources of funding that are drying up elsewhere. But the other is the very real desire that many scientists have to see the fruits of their labor—the products of their intellectual endeavor—really translated into a human good. It's wrong to underestimate the desire of a scientist to see what he or she has done really put to favorable use." — Phil Leder, Focus, September 6, 1996
Many are concerned about the potential for abuse in a system in which the prospect of monetary gain drives decisions about which projects to pursue. There are worries that the academic tradition of free sharing of information will suffer and that public confidence in the research enterprise will erode. But the increasing expense of supporting research and limited available alternatives make industrial partnerships a viable solution for many universities.
"…it turns out that the [commercial] partnership can supply funding for research that may not be available through an NIH grant. In the NIH system, it is rare to be able to fund an idea that is very new, and has little or no preliminary data. Some of our more surprising findings were made with industrial funding." — Judah Folkman, from Harvard University's Focus, September 6, 1996
Societies
1979: Leder is elected into the National Academy of Science.
Honors
1954: Leder receives the Detur Award for academic excellence.
1987: Leder receives the Albert Lasker Basic Medical Research Award.
1991: Leder receives the National Medal of Science.
Published Work
Philip Leder, David A. Clayton, Edward Rubenstein (Ed.): Scientific American Introduction to Molecular Medicine (Basic Science for Clinicians Series).
Leder, P. The genetics of antibody diversity. Scientific American. (May) 1982; 246: 86-93.
Martin SS, Leder P.: Human mcf10a mammary epithelial cells undergo apoptosis following actin depolymerization that is independent of attachment and rescued by bcl-2. Mol Cell Biol. 2001 Oct;21(19):6529-36.
Goodwin NC, Ishida Y, Hartford S, Wnek C, Bergstrom RA, Leder P, Schimenti JC.: DelBank: a mouse ES-cell resource for generating deletions. Nat Genet 2001 Aug;28(4):310-311.
Michaelson JS, Leder P.: beta-catenin is a downstream effector of Wnt-mediated tumorigenesis in the mammary gland. Oncogene. 2001 Aug 23;20(37):5093-9.
Vollrath B, Fitzgerald KJ, Leder P.: A murine homologue of the Drosophila brainiac gene shows homology to glycosyltransferases and is required for preimplantation development of the mouse. Mol Cell Biol. 2001 Aug;21(16):5688-97.
Brodie SG, Xu X, Li C, Kuo A, Leder P, Deng CX.: Inactivation of p53 tumor suppressor gene acts synergistically with c-neu oncogene in salivary gland tumorigenesis. Oncogene. 2001 Mar 22;20(12):1445-54.
Lebel M, Cardiff RD, Leder P.: Tumorigenic effect of nonfunctional p53 or p21 in mice mutant in the Werner syndrome helicase. Cancer Res. 2001 Mar 1;61(5):1816-9.
Weiss, R.S., Enoch, T., and Leder, P.: Inactivation of mouse Hus1 results in genomic instability and impaired responses to genotoxic stress. Genes & Development 14: 1886-1898 (2000).
Weinstein EJ, Kitsberg DI, Leder P.: A mouse model for breast cancer induced by amplification and overexpression of the neu promoter and transgene. Mol Med. 2000 Jan;6(1):4-16.
Lebel M, Spillare EA, Harris CC, Leder P.: The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J Biol Chem 1999 Dec 31;274(53):37795-37799.
Fitzgerald, K., Harrington, A., and Leder, P.: Ras pathway signals are required for Notch-mediated oncogenesis. Oncogene 29: 4191-4198 (2000).
Ishida, Y. and Leder, P.: RET: a poly A-trap retrovirus vector for reversible disruption and expression monitoring of genes in living cells. Nucl. Acids Res. 27: e35 (1999).
P. Leder. The Genetics of Antibody Diversity. In W.E. Paul, editor, Immunology: Recognition and Response. W. H. Freeman, New York, 1991.
Shen, MM; Skoda, RC; Cardiff, RD; Campos-Torres, J; Leder, P; Ornitz, DM. Expression of LIF in transgenic mice results in altered thymic epithelium and apparent interconversion of thymic and lymph node morphologies. Embo Journal, 1994 Mar 15, 13(6):1375-85.
Cardiff, RD; Leder, A; Kuo, A; Pattengale, PK; Leder, P. Multiple tumor types appear in a transgenic mouse with the ras oncogene. American Journal of Pathology, 1993 Apr, 142(4):1199-207.
Benvenisty, N; Ornitz, DM; Bennett, GL; Sahagan, BG; Kuo, A; Cardiff, RD; Leder, P. Brain tumours and lymphomas in transgenic mice that carry HTLV-I LTR/c-myc andn Ig/tax genes. Oncogene, 1992 Dec, 7(12):2399-405.
Ornitz, DM; Cardiff, RD; Kuo, A; Leder, P. Int-2, an autocrine and/or ultra-short-range effector in transgenic mammary tissue transplants. Journal of the National Cancer Institute, 1992 Jun 3, 84(11):887-92.
Cardiff, RD; Sinn, E; Muller, W; Leder, P. Transgenic oncogene mice: Tumor phenotype predicts genotype. American Journal of Pathology, 1991 Sep, 139(3):495-501.
Leder, A; Kuo, A; Cardiff, RD; Sinn, E; Leder, P. Hv-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: effects of phorbol esters and retinoic acid. Proceedings of the National Academy of Sciences of the United States of America, 1990 Dec, 87(23):9178-82.
Max, E. E., Maizel, J. V., Jr., Leder, P. The Nucleotide Sequence of a 5.5-kilobase DNA Segment Containing the Mouse k Immunoglobulin J and C Region Genes. Journal of Biological Chemistry. 256: 5116-5120, 1981.
Max, E. E., Seidman, J. G., Leder, P. Sequences of Five Potential Recombination Sites Encoded Close to an Immunoglobulin k Constant Region Gene. Proceedings of the National Academy of Sciences 76: 3450-3454, 1979.
Other References
A Look at the Work of Frontline Scientists and How They Are Changing Medicine. Johns Hopkins University Press, Howard Hughes Medical Institute, 2000.
Who Wrote the Book of Life? A History of the Genetic Code by Lily Kay; Stanford University Press, 2000.
The Eighth Day of Creation: Makers of the Revolution in Biology by Horace Freeland Judson; Cold Spring Harbor Laboratory Press; revised and expanded edition, 1996.
A Century of DNA: A History of the Discovery of the Structure and Function of the Genetic Substance by Franklin Portugal.
French, John E., Spalding, Judson W, Tennant, Raymond W., "Identifying Chemical Carcinogenicity and Assessing Potential Risk in Short Term Bioassays Using Transgenic Mouse Models"; Environmental Health Perspective, Journal of the National Institute of Environmental Health Sciences: Vol. 103, #10: Oct. 1995.