Stanley Michael Gartler

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Stanley Michael Gartler
Stanley Michael Gartler 2009.jpg
Born (1923-06-09) June 9, 1923 (age 100)
Los Angeles, California, U.S.
Education UCLA, 9th Air Force, UC Berkeley
Known forOffering conclusive evidence for the clonality of human cancers
SpouseMarion Mitchelson Gartler
Scientific career
FieldsGenetics
InstitutionsUC Berkeley

Columbia University

University of Washington School of Medicine
Academic advisors Curt Stern

Stanley Michael Gartler (born June 9, 1923) is an American cell and molecular biologist and human geneticist. He was the first scientist to offer conclusive evidence for the clonality of human cancers. He showed that HeLa cells had contaminated many cell lines thought to be unique. Stanley Gartler is currently Professor Emeritus of Medicine and Genome Sciences at the University of Washington.

Contents

Biography

Gartler was born in Los Angeles, California in 1923 [1] of Romanian immigrant parents George Gartler and Delvira Kupferberg. Gartler's sister, Adeline Gartler, was born on September 26, 1921.

Gartler attended public school in Los Angeles and completed two years at university (UCLA) before enlisting in the Army Air Force during World War II. [1] He served as a radio operator and machine gunner on a B-26, and flew combat missions with the 9th Air Force. [2] After the war, on the G.I. Bill, he completed his undergraduate education at UCLA in agriculture. He met his future wife, Marion Mitchelson, at a New Year’s Eve party in 1947 and the two were married in November 1948. [3] After spending a year working on a farm in the San Joaquin Valley, Gartler entered the Ph.D. program in Genetics at UC Berkeley in 1949. [2] [3] He originally intended to apply genetics for agricultural uses, but near the end of his graduate work, he made a career switch and decided to enter the field of human genetics after enrolling in a course taught by Curt Stern. [1]

In 1952 Gartler began a public health postdoctoral fellowship at Columbia University to study human genetics, [4] which he completed over the course of five years. [3] [2] In 1957 Gartler was recruited by Arno G. Motulsky to join his newly established Division of Medical Genetics in the Department of Medicine at the University of Washington in Seattle. [1] [2] [5] Gartler was a founding member of the Department of Genetics at the University of Washington in 1959. [4] Stanley became a professor emeritus in 1993. [2]

Commemorative plaque honoring the founding members of the University of Washington Division of Medical Genetics, Arno Motulsky and Stanley Gartler PXL 20220914 181416412.MP.jpg
Commemorative plaque honoring the founding members of the University of Washington Division of Medical Genetics, Arno Motulsky and Stanley Gartler

Work

In 1965, Stanley Gartler and collaborator David Linder were able to demonstrate clonality of tumors in human females using an event (X chromosome inactivation) that occurs early in development in mammalian females. X chromosome inactivation randomly silences most of the genes on one of the two X chromosomes in every cell of the embryo. The female thus becomes a mosaic for any X-linked gene for which she is heterozygous, and normal tissues are consequently composed of a nearly equal mixture of cells expressing the two different phenotypes. [6] Gartler reasoned that, if a tumor begins from a single cell, then all the cells of that tumor should express the same, single X-linked allele. By examining expression of different isoenzymes of the sex-linked glucose-6-phosphate dehydrogenase (G6PD) locus in heterozygous women, Gartler and Linder demonstrated that leiomyoma tumor cells, even those from cancers consisting of billions of cells, expressed only one form of the marker, whereas even small patches of normal tissue contained cells expressing both forms of the marker. This finding was consistent with the growth of a single founder cell into a tumor. [7] [8] The clonal origin of various tumors has been confirmed many times since, both initially through Gartler's work with a junior colleague, Philip J. Fialkow, [9] [10] and by other groups.

In 1967, Gartler became interested in establishing a system for studying human genetics in somatic cell culture. He initially studied eighteen (supposedly) independently derived established human cell lines obtained from the American Type Culture Collection, including HeLa. Examining isoenzymes, he typed them for a number of genetic polymorphisms, including the X-linked G6PD variant. The cell lines turned out to be genetically identical, and moreover, all carried the G6PD allele found almost exclusively in people of African descent. HeLa, which was the first successfully established human cell line, was derived from a woman of African descent named Henrietta Lacks, so this result suggested that the cell lines were not truly independent, but had instead been contaminated by HeLa cells. [11] [12]

It was not realized at the time that nearly all attempts to establish human cell cultures resulted in cell lines with limited life spans. Dr. George Gey, the originator of HeLa, had sent those cells to all who requested them, and the contamination problem arose because many workers were growing the immortal HeLa cell and mortal human cell strains in close proximity. Since the use of genetic markers to characterize and distinguish cell lines at the time was virtually non-existent, contamination events from HeLa went undetected. In spite of the evidence, initially, the idea of laboratory errors leading to cross culture contamination was not universally accepted: an alternative explanation was that, when cultures became established, their G6PD phenotype changed. [13] Gartler's original paper to Nature went to lengths to dismiss this possibility, surveying over 100 tumors to see if there was a phenotypic change in either G6PD or PGM, as well as trying other experimental approaches to test the idea. He concluded that "all evidence seems to point to the stability of the G6PD and PGM phenotypes both in vivo and in vitro." [12] Further evidence against the possibility of phenotypic conversion came when Nellie Auesperg and Gartler identified a truly independently established human cell line, which they showed to exhibit unique genetic markers.

Cross-culture contamination is now a generally accepted risk in establishing cell lines, and there are many genetic markers available to accurately characterize human cell cultures. However, the problem of cross-culture contamination has not been eliminated. Walter Nelson-Rees took up the issue some ten years after the original Gartler report, and continued to write about the problem for almost 25 years.

Gartler's later career reflected his continued interest in the X chromosome and X inactivation. Such work included discovery of the presence of two functional X chromosomes within oocytes, [14] demonstrating the association between fragile X syndrome and delayed replication of FMR1 [15] [16] , and identification of DNMT3B as the gene underlying Immunodeficiency–centromeric instability–facial anomalies syndrome, [17] the first recognized human hypomethylation disease.

In 1991, evolutionary biologist Leigh Van Valen put forth an argument that the HeLa cell line constituted a new microbial species, which he proposed be designated Helacyton gartleri, in recognition of Gartler's work. [18]

Honors

Related Research Articles

<span class="mw-page-title-main">HeLa</span> Oldest cultured human cell line (1951)

HeLa is an immortalized cell line used in scientific research. It is the oldest human cell line and one of the most commonly used. HeLa cells are durable and prolific, allowing for extensive applications in scientific study. The line is derived from cervical cancer cells taken on 8 February 1951, from Henrietta Lacks, a 31-year-old African American mother of five, after whom the line is named. Lacks died of cancer on 4 October 1951.

<span class="mw-page-title-main">Yeast artificial chromosome</span> Genetically engineered chromosome derived from the DNA of yeast

Yeast artificial chromosomes (YACs) are genetically engineered chromosomes derived from the DNA of the yeast, Saccharomyces cerevisiae, which is then ligated into a bacterial plasmid. By inserting large fragments of DNA, from 100–1000 kb, the inserted sequences can be cloned and physically mapped using a process called chromosome walking. This is the process that was initially used for the Human Genome Project, however due to stability issues, YACs were abandoned for the use of bacterial artificial chromosome

<span class="mw-page-title-main">Mosaic (genetics)</span> Condition in multi-cellular organisms

Mosaicism or genetic mosaicism is a condition in which a multicellular organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized egg. Mosaicism is one of several possible causes of chimerism, wherein a single organism is composed of cells with more than one distinct genotype.

Comparative genomic hybridization (CGH) is a molecular cytogenetic method for analysing copy number variations (CNVs) relative to ploidy level in the DNA of a test sample compared to a reference sample, without the need for culturing cells. The aim of this technique is to quickly and efficiently compare two genomic DNA samples arising from two sources, which are most often closely related, because it is suspected that they contain differences in terms of either gains or losses of either whole chromosomes or subchromosomal regions. This technique was originally developed for the evaluation of the differences between the chromosomal complements of solid tumor and normal tissue, and has an improved resolution of 5–10 megabases compared to the more traditional cytogenetic analysis techniques of giemsa banding and fluorescence in situ hybridization (FISH) which are limited by the resolution of the microscope utilized.

<span class="mw-page-title-main">Cell culture</span> Process by which cells are grown under controlled conditions

Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. After cells of interest have been isolated from living tissue, they can subsequently be maintained under carefully controlled conditions. They need to be kept at body temperature (37 °C) in an incubator. These conditions vary for each cell type, but generally consist of a suitable vessel with a substrate or rich medium that supplies the essential nutrients (amino acids, carbohydrates, vitamins, minerals), growth factors, hormones, and gases (CO2, O2), and regulates the physio-chemical environment (pH buffer, osmotic pressure, temperature). Most cells require a surface or an artificial substrate to form an adherent culture as a monolayer (one single-cell thick), whereas others can be grown free floating in a medium as a suspension culture. This is typically facilitated via use of a liquid, semi-solid, or solid growth medium, such as broth or agar. Tissue culture commonly refers to the culture of animal cells and tissues, with the more specific term plant tissue culture being used for plants. The lifespan of most cells is genetically determined, but some cell-culturing cells have been 'transformed' into immortal cells which will reproduce indefinitely if the optimal conditions are provided.

<span class="mw-page-title-main">X-inactivation</span> Inactivation of copies of X chromosome

X-inactivation is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a transcriptionally inactive structure called heterochromatin. As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome.

<span class="mw-page-title-main">Small supernumerary marker chromosome</span> Abnormal partial or mixed chromosome

A small supernumerary marker chromosome (sSMC) is an abnormal extra chromosome. It contains copies of parts of one or more normal chromosomes and like normal chromosomes is located in the cell's nucleus, is replicated and distributed into each daughter cell during cell division, and typically has genes which may be expressed. However, it may also be active in causing birth defects and neoplasms. The sSMC's small size makes it virtually undetectable using classical cytogenetic methods: the far larger DNA and gene content of the cell's normal chromosomes obscures those of the sSMC. Newer molecular techniques such as fluorescence in situ hybridization, next generation sequencing, comparative genomic hybridization, and highly specialized cytogenetic G banding analyses are required to study it. Using these methods, the DNA sequences and genes in sSMCs are identified and help define as well as explain any effect(s) it may have on individuals.

<span class="mw-page-title-main">George Otto Gey</span> American cell biologist (1899–1970)

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<span class="mw-page-title-main">ST7</span> Human protein and coding gene

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HUMARA assay is one of the most widely used methods to determine the clonal origin of a tumor. The method is based on X chromosome inactivation and it takes advantage of the different methylation status of the gene HUMARA located on the X chromosome. Considering the fact that once one X chromosome is inactivated in a cell, all other cells derived from it will have the same X chromosome inactivated, this approach becomes a tool to differentiate a monoclonal population from a polyclonal one in a female tissue. The HUMARA gene, in particular, has three important features that make it highly convenient for the purpose:

  1. The gene is located on the X chromosome and it goes through inactivation by methylation in normal embryogenesis of a female infant. Because most genes on the X chromosome undergo inactivation, this feature is important.
  2. Human androgen receptor gene alleles have varying numbers of CAG repeats. Thus, when DNA from a healthy female tissue is amplified by polymerase chain reaction (PCR) for a specific region of the gene, two separated bands can be seen on the gel.
  3. The region that is amplified by PCR also has certain base orders that make it susceptible to be digested by HpaII enzyme when it is not methylated. This detail gives the opportunity to researchers to differentiate a methylated allele from the unmethylated allele.

Robert Williamson is a retired British-Australian molecular biologist who specialised in the mapping, gene identification, and diagnosis of human genetic disorders.

References

  1. 1 2 3 4 5 "On the cover". American Journal of Human Genetics. 96 (3): On the cover. 2015-03-05.
  2. 1 2 3 4 5 Jarvik, Gail P. (2017-03-02). "2016 Victor A. McKusick Leadership Award Introduction: Stanley Gartler". American Journal of Human Genetics. 100 (3): 401–402. doi:10.1016/j.ajhg.2017.01.012. ISSN   0002-9297. PMC   5339076 . PMID   28257688.
  3. 1 2 3 "Marion Mitchelson Gartler". funerals.coop. Retrieved 2023-04-16.
  4. 1 2 Gartler, Stanley M. (2017-03-02). "2016 Victor A. McKusick Leadership Award". American Journal of Human Genetics. 100 (3): 403–405. doi:10.1016/j.ajhg.2017.01.010. ISSN   1537-6605. PMC   5339078 . PMID   28257689.
  5. ↑ Motulsky, Arno G.; King, Mary-Claire (2016-08-31). "The Great Adventure of an American Human Geneticist". Annual Review of Genomics and Human Genetics. 17: 1–15. doi: 10.1146/annurev-genom-083115-022528 . ISSN   1545-293X. PMID   27147253.
  6. ↑ Gartler, SM & Linder, D. 1964. Selection in mammalian mosaic cell populations. Cold Spring Harb Symp Quant Biol 29: 253-260
  7. ↑ Linder, D & Gartler, SM. 1965 Glucose-6-phosphate dehydrogenase mosaicism: utilization as a cell marker in the study of leiomyomas. Science 150:67-69
  8. ↑ Linder D & Gartler, SM. 1965 Problem of single cell versus multicell origin of a tumor. Proc 5th Berkeley Symp Math Stat & Prob 625-633
  9. ↑ Fialkow, P. J.; Gartler, S. M.; Yoshida, A. (October 1967). "Clonal origin of chronic myelocytic leukemia in man". Proceedings of the National Academy of Sciences of the United States of America. 58 (4): 1468–1471. Bibcode:1967PNAS...58.1468F. doi: 10.1073/pnas.58.4.1468 . ISSN   0027-8424. PMC   223947 . PMID   5237880.
  10. ↑ Fialkow, P. J.; Klein, G.; Gartler, S. M.; Clifford, P. (1970-02-21). "Clonal origin for individual Burkitt tumours". Lancet. 1 (7643): 384–386. doi:10.1016/s0140-6736(70)91517-5. ISSN   0140-6736. PMID   4189689.
  11. ↑ Gartler, SM. 1967 Genetic markers as tracers in cell culture. Nat Cancer Inst Monogr 26: 167-195
  12. 1 2 Gartler, SM. 1968 Apparent HeLa cell contamination of human heteroploid cell lines. Nature 217:750-751
  13. ↑ Auersperg N & Gartler SM. 1970 Isozyme stability in human heteroploid cell lines. Exp Cell Res 61:455-457
  14. ↑ Gartler, S. M.; Liskay, R. M.; Gant, N. (December 1973). "Two functional X chromosomes in human fetal oocytes". Experimental Cell Research. 82 (2): 464–466. doi:10.1016/0014-4827(73)90368-6. ISSN   0014-4827. PMID   4765252.
  15. ↑ Hansen, R. S.; Canfield, T. K.; Lamb, M. M.; Gartler, S. M.; Laird, C. D. (1993-07-02). "Association of fragile X syndrome with delayed replication of the FMR1 gene". Cell. 73 (7): 1403–1409. doi: 10.1016/0092-8674(93)90365-w . ISSN   0092-8674. PMID   8324827. S2CID   12420098.
  16. ↑ Hansen, R. S.; Canfield, T. K.; Fjeld, A. D.; Mumm, S.; Laird, C. D.; Gartler, S. M. (1997-04-29). "A variable domain of delayed replication in FRAXA fragile X chromosomes: X inactivation-like spread of late replication". Proceedings of the National Academy of Sciences of the United States of America. 94 (9): 4587–4592. Bibcode:1997PNAS...94.4587H. doi: 10.1073/pnas.94.9.4587 . ISSN   0027-8424. PMC   20767 . PMID   9114034.
  17. ↑ Hansen, R. S.; Wijmenga, C.; Luo, P.; Stanek, A. M.; Canfield, T. K.; Weemaes, C. M.; Gartler, S. M. (1999-12-07). "The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome". Proceedings of the National Academy of Sciences of the United States of America. 96 (25): 14412–14417. Bibcode:1999PNAS...9614412H. doi: 10.1073/pnas.96.25.14412 . ISSN   0027-8424. PMC   24450 . PMID   10588719.
  18. ↑ Maiorana VC, Van Valen LM (7 February 1991). "Hela, a new microbial species" (PDF). Evolutionary Theory. 10 (2): 71–74.
  19. ↑ "Stanley M. Gartler". www.nasonline.org. Retrieved 2023-04-15.
  20. ↑ Puga, Christelle (2016-06-30). "ASHG Honors Stanley Gartler with Victor A. McKusick Leadership Award". ASHG. Retrieved 2023-04-16.
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