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Developmental Biology Using Purified Genes

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Developmental Biology Using Purified Genes LASKER~KOSHLAND SPECIAL ACHIEVEMENT ESSAY IN MEDICAL SCIENCE AWARD Developmental biology using purified genes Donald D Brown Some history Control Anucleolate Magnesium From the NIH I went to the Pasteur Institute mutant deficient After three years of college I entered the in Paris to study bacterial gene regulation in University of Chicago Medical School in the 1959, the year after the Lac repressor had been fall of 1952 and discovered biochemistry and discovered. Before leaving Bethesda, by the research. Lloyd Kozloff, a member of the greatest luck I learned about a small research bacteriophage group in the Department of institution in Baltimore that was associated Biochemistry, guided my research. While in at that time with the Johns Hopkins Medical medical school I began searching for a future School called the Department of Embryology of research subject, thinking it should be an the Carnegie Institution of Washington. I con- important medically related problem but unex- tacted Jim Ebert, the director, and arranged an plored by what were then the modern methods advanced postdoctoral fellowship after my year of biochemistry. in Paris. It is hard to imagine two more diverse The field of embryology, newly named research institutions. ‘developmental biology’, caught my attention. The Pasteur Institute was at the forefront of Reproductive biology was barely discussed, biology, involved in the founding of molecular and descriptive embryology was taught in two biology. Every day at lunch Jacques Monod, lectures as a part of gross anatomy. In 1953, I François Jacob and André Lwoff presided attended a biochemistry journal club discus- over an exciting discussion usually augmented Figure 1 Comparison of control (left), anucleolate sion of the Watson-Crick Nature paper describ- by a prominent visitor. The Department of mutant (center) and magnesium-deficient (right) ing the structure of DNA. I knew immediately Embryology was just phasing out 50 years of embryos of X. laevis after four days of that my future would involve some merger of describing the anatomical development of the development. Magnesium deficiency arrests DNA research, biochemistry and the field of human embryo. The faculty was principally embryos at the same stage of development as the embryology. engaged in experimental embryology. I was the anucleolate mutant. From ref. 2. After an internship at Charity Hospital in first biochemist. This is how I came to spend By the early 1960s, sucrose-gradient centrifuga- New Orleans and my wedding, my wife and I 50 years pursuing the topic of gene regulation tion had been devised to separate by size three moved to Bethesda, Maryland. My two years in development at the Carnegie Institution’s general classes of RNA, the 18S and 28S rRNA, of service were fulfilled as a member of the first Department of Embryology in Baltimore. I low molecular weight RNAs and a very hetero- class of ‘research associates’ at the US National cannot imagine a more ideal place. geneous DNA-like RNA that was presumed to Institutes of Health (NIH). I spent two wonderful include the newly discovered mRNA. I found years in the Institute of Mental Health as part of The isolation of genes before the that the three size classes of RNA were synthe- a project organized by Seymour Kety to investi- recombinant DNA era sized at vastly different rates during develop- gate systematically the metabolism of molecules I choose embryos of the frog Rana pipiens to ment. Even though the unfertilized frog egg is a that had been implicated in schizophrenia. I study because the eggs could be fertilized in single cell, it has as many ribosomes as the same was assigned to study the urinary metabolites vitro and the embryos developed synchronously weight of a multicellular somatic tissue such as of the amino acid histidine because it was the and provided unlimited amounts of material the liver. New rRNA was not synthesized until precursor of one such compound—histamine. I for biochemistry. While I was at the Pasteur the embryo had developed to 10,000 cells, and ended my two years by feeding 10 microCuries Institute, two separate groups discovered mes- new ribosomes did not contribute substantially of 14C-histidine to ten healthy controls and ten senger RNA (mRNA), and it had become clear to the total content of ribosomes until several people with schizophrenia, collecting their urine from studies with bacteria that ribosomal RNA days later. and analyzing the radioactive products. Then I (rRNA) and transfer RNAs were direct gene My first discovery at Carnegie was that frog published one of the few negative studies on the products. Previously, ‘differential gene action’ embryos do not develop in distilled water. They subject of the biochemical basis of schizophrenia. had been studied in embryos as fluctuations need four cations—calcium, sodium, potassium in enzymatic activity that was assumed to and magnesium, in that order during develop- Donald D. Brown is in the Department of represent changes in the amount of a protein. ment. Magnesium deficiency was especially Embryology, Carnegie Institute for Science, I realized that, as RNA was closer to the gene interesting because, without it, embryos develop Baltimore, Maryland, USA. than protein was, its analysis would be a more for several days and arrest as early swimming e-mail: [email protected] reliable reflection of gene expression changes. tadpoles at the same stage that a frog embryo xxvi VOLUME 18 | NUMBER 10 | OCTOBER 2012 NATURE MEDICINE ESSAY different base composition for the next decade. was the first example of a class of transcription It led to the purification of X. laevis ribosomal factors called zinc finger proteins15. DNA (rDNA) by Birnstiel. This was the first iso- lation of a gene from any organism. In 1966, at Silk fibroin mRNA and its gene a symposium on the nucleolus in Montevideo, The discovery of gene amplification in 1968 Uruguay, Oscar Miller showed electron micro- encouraged us to ask whether this mechanism graphs of genes in the nuclei of amphibian is used more broadly when a cell synthesizes a oocytes transcribing RNA4. These genes were large amount of a gene product. I had read about the size predicted for the rRNA genes, and they the unusual amino acid sequence and the huge came from the thousands of nucleoli in each size of the protein silk fibroin from the silkworm oocyte nucleus (Fig. 2). As the oocyte is a tetra- Bombyx mori. Most of the protein consists of ploid cell and should have just four nucleoli, we repeats of the peptide glycine-alanine-glycine- predicted that these extra nucleoli must contain alanine-glycine-serine, which predicts an many extra genes encoding rRNA. Igor Dawid mRNA and gene with a very high guanine and and I5 and, independently, Joe Gall6 showed the cytosine content. At the end of larval develop- Figure 2 An isolated nucleus from a mature ‘specific amplification’ of the genes encoding the ment, most of the protein synthesized by the oocyte of X. laevis. The diameter of the nucleus is 18S and 28S rRNAs in amphibian oocyte nuclei. posterior end of the silk gland is this single pro- about 400 µm. Cresyl violet stain accentuates the tein. At that time, only hemoglobin mRNA in thousands of nucleoli. From ref. 5. We learned that the genes encoding the 5S rRNAs are not linked to the rRNA genes but reticulocytes had been identified on a sucrose begins to increase its total amount of rRNA. It comprise an even greater fraction of the genome gradient as a discrete mRNA. Yoshiaki Suzuki was well known that magnesium holds ribo- of X. laevis DNA than does the rDNA. We puri- came to my lab as a postdoctoral fellow, and we somes together. In 1962, I read an article about fied and studied the 5S rRNA genes (5S DNA) began to raise silk worms. He isolated a large a mutant of the South African clawed toad from the X. laevis genomic DNA in 1971 (ref 7), 32P-labeled mRNA from the posterior silk gland Xenopus laevis that had an altered number of taking advantage of the unusual base composi- by sucrose-gradient centrifugation. Partial nucleoli1. The wild type had two nucleoli in tion of the many tandemly repeated 5S rRNA sequencing identified the predicted unusual each nucleus; the heterozygote had one nucleo- genes. These small genes were especially use- sequence of the silk fibroin mRNA16. The lus and was perfectly normal. Crossing two het- ful for detailed characterization and functional radioactive mRNA was pure enough to hybrid- erozygotes yielded a typical Mendelian ratio of studies in the days before DNA sequencing and ize with DNA from the posterior silk gland and offspring in which one-quarter of the progeny recombinant DNA methods were available. We from control silkworm tissues to show that there were anucleolate. These homozygous mutants learned that spacer DNA separated tandem is a single fibroin gene in the DNA of all cell arrested development exactly at the stage of a genes (Fig. 3). In different species of Xenopus the types. This ruled out DNA amplification as an normal embryo deprived of magnesium (Fig. 1), spacers were very different, whereas the genes explanation for the large and specific synthesis suggesting to me that the mutation affected the were highly conserved. Yet the spacers within a of silk fibroin mRNA by the posterior gland. synthesis of new ribosomes. species were remarkably similar, a phenomenon Silk protein synthesis is an example of extreme The only source of this mutant was the that we called horizontal evolution. Within each translational amplification. In a period of only Oxford lab where it had been discovered. 5S rRNA gene repeat there is a pseudogene. two to three days, each fibroin gene guides the Meanwhile, I learned that X.
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