Gene pioneers: Donald Brown and Thomas Maniatis win the 2012 Lasker~Koshland Special Achievement Award in Medical Science Kathryn Claiborn J Clin Invest. 2012;122(10):3383-3386. https://doi.org/10.1172/JCI66476. News The 2012 Lasker~Koshland Special Achievement Award in Medical Science recognizes Donald Brown (Carnegie Institute of Washington) and Thomas Maniatis (Columbia University) (Figure 1), two scientists whose career-long contributions were seminal to our understanding of what genes are and our ability to study and manipulate them, and whose commitment to mentorship have had tremendous impact on a generation of scientists. What is a gene? In the nineteenth century, an Austrian monk began a set of experiments in a small garden plot. Gregor Mendel’s detailed study of garden peas led him to understand that visible traits, such as the height or color of a plant, were determined by the combined inheritance of two physical particles from the two parent plants. Decades later, Theodor Boveri and Walter Sutton, analyzing meiotic cell divisions in grasshopper testes with the help of a microscope, hypothesized that Mendel’s hereditary factors — genes — could be carried on chromosomes. The groundwork was thus laid for a basic understanding of inheritance, but the question remained: what is a gene, exactly? Further understanding these entities — both their molecular makeup and their regulation — would require the dedication of innumerable scientific careers, as well as technical innovations that allowed the isolation and manipulation their sequences.Development As a young man, Don Brown elected to follow in his father’s footsteps and study […] Find the latest version: https://jci.me/66476/pdf News Gene pioneers: Donald Brown and Thomas Maniatis win the 2012 Lasker~Koshland Special Achievement Award in Medical Science T he 2012 Lasker~Koshland Special Following his medical internship, Brown I was at the Pasteur Institute, two groups real- Achievement Award in Medical Science pursued those research interests at the NIH, ized that transfer RNAs, ribosomal RNAs, recognizes Donald Brown (Carnegie Insti- where he joined a group working to uncover and structural RNAs were in fact gene prod- tute of Washington) and Thomas Mania- the molecular basis for schizophrenia, and ucts just like messenger RNA.” A mutant tis (Columbia University) (Figure 1), two later at the Pasteur Institute in Paris, where strain of the frog Xenopus laevis had been scientists whose career-long contribu- he worked with Jacques Monod on the con- described by a group at Oxford that could tions were seminal to our understanding trol of gene expression in bacteria. Through- produce embryos lacking a structure within of what genes are and our ability to study out these diverse experiences, though, he the nucleus called the nucleolus, and Brown and manipulate them, and whose commit- knew that his deepest interest lay in under- began a collaborating with John Gurdon ment to mentorship have had tremendous standing development and embryology. to study them. These mutants died in the impact on a generation of scientists. He remembered, “I felt like it was a huge middle of embryogenesis — the same time, medically related problem, and not many Brown knew, that cells normally accumulate What is a gene? people were working on it.” Upon returning large amounts of ribosomal RNA. Working In the nineteenth century, an Austrian monk from Paris in 1960, he joined the embryol- together, Brown and Gurdon discovered that began a set of experiments in a small garden ogy department at the Carnegie Institute of the anucleolar embryos were failing to make plot. Gregor Mendel’s detailed study of gar- Washington, a place where his biochemistry ribosomal RNA, establishing a critical role den peas led him to understand that visible background and exposure to the emerging for the nucleolus in this process (2). traits, such as the height or color of a plant, science of molecular biology set him apart. Later, Brown became aware of another were determined by the combined inheri- “In those days, people talked a lot about interesting anomaly of the frog oocyte. The tance of two physical particles from the two ‘a change in gene activity,’ and what they cells contain a huge number of ribosomes parent plants. Decades later, Theodor Boveri meant was a change in enzymatic activity. before fertilization (by comparison, the and Walter Sutton, analyzing meiotic cell But it seemed to me that if one was going to cells contain as many ribosomes as might divisions in grasshopper testes with the help study gene activity, it would be reasonable to be found in a million liver cells), and the of a microscope, hypothesized that Mendel’s try to be closer to the gene and study RNA number of nucleoli in those oocytes was hereditary factors — genes — could be car- changes rather than protein changes.” also amplified (Figure 2). As he explained, ried on chromosomes. The groundwork was Thus, Brown embarked on his independent “Xenopus cells have one nucleolus per hap- thus laid for a basic understanding of inheri- research using frog oocytes and embryos as a loid complement; oocytes are tetraploid, tance, but the question remained: what is a model system. He became interested in ribo- so they should have four nucleoli, but they gene, exactly? Further understanding these somes, and specifically the production of don’t: they have thousands.” His group, entities — both their molecular makeup and ribosomal RNA, during development. “While and coincidently Joseph Gall’s laboratory their regulation — would require the dedica- tion of innumerable scientific careers, as well as technical innovations that allowed the iso- lation and manipulation their sequences. Development As a young man, Don Brown elected to follow in his father’s footsteps and study medicine, and enrolled at the University of Chicago. At the time, he had not con- sidered pursuing a research career, but the curriculum was research intensive, and it caught his interest. Further cementing his direction, Brown heard a journal club presentation of James Watson and Fran- cis Crick’s 1953 description of the dou- ble helix (1). “That really excited me,” he said in a recent interview with the JCI, “I got more interested in biochemistry and Figure 1 research than I was in medical school. I did Donald Brown (left) and Thomas Maniatis (right) won the 2012 Lasker~Koshland Special research every free moment.” Achievement Award in Medical Science. The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 10 October 2012 3383 news ate studies at Vanderbilt University, under in Cambridge, Maniatis moved his research the tutelage of Leonard Lerman. There he program to Caltech. While there, he contin- studied the structure of compacted DNA ued to develop new methods for the isola- by small-angle X-ray scattering and through tion and manipulation of gene products. his reading developed a strong interest in This included the generation of genomic gene regulation. Eventually this interest led DNA libraries — collections of recombinant him to a postdoctoral position in the lab of bacteriophage that as a set contained all of Mark Ptashne at Harvard University, where the DNA sequence present in the genome he worked on bacteriophage lambda repres- — which made it possible for researchers sor interactions with DNA and discovered to easily identify and isolate any gene. As multiple binding sites within the operator this work was opening new opportunities (6). Maniatis’s postdoctoral work was an to biologists interested in genes and gene important impetus to his later discoveries; regulation, Jim Watson invited Maniatis as he recently told the JCI, “It was through back to Cold Spring Harbor to teach a sum- that study that I really developed a desire to mer course on molecular cloning. With his do similar things in eukaryotic cells; but at postdoctoral fellow Edward Fritsch, Mania- Figure 2 the time that wasn’t possible, because we tis assembled experimental protocols to cre- A mature oocyte from Xenopus laevis. Cre- didn’t have the technology.” ate the course manual. Later, Fritsch and syl violet stain accentuates the thousands of A chance meeting with a young physi- Maniatis worked with Joseph Sambrook to nucleoli. Reproduced with permission from cian, Argiris Efstratiadis, then a student in adapt the course manual into a book, Molec- Science (3). Fotis Kafatos’s lab, would quickly change ular Cloning: A Laboratory Manual, which has that. Maniatis and Efstratiadis began col- since become an invaluable resource in laborating on a project to clone cDNAs — molecular biology labs worldwide (10). at Yale University, found that this was due DNA copies of transcription products. Remarkably, Maniatis recalls not antici- to a dramatic amplification of ribosomal They succeeded in isolating full-length pating the impact this manual would have. RNA gene number (3, 4). DNA copies of β-globin gene mRNA, a key “The only person who really appreciated These amplified genes, then, were a step toward establishing a system in which that was Jim Watson,” he said. “We were good source from which to attempt gene they could study gene regulation (7, 8). all so busy with our own research and with sequence isolation. A few years later, in 1971, Standing between them and the next step, the job of writing the manual. It required Brown and his group were able to isolate the however, was a surprising hurdle: the City an enormous amount of work, and wasn’t 5s ribosomal genes (5). Just the second gene Council of Cambridge, Massachusetts. simply putting together a bunch of proto- sequences to be isolated, the 5s ribosomal In the mid-1970s, the Cambridge City cols, because at the time, there were no kits genes were the basis for many of the stud- Council instituted a moratorium on recom- out there, no easy ways to do things.