The Sui Generis Sydney Brenner,” by Thoru Pederson, Which Was First Published June 10, 2019; 10.1073/ Pnas.1907536116 (Proc
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Correction RETROSPECTIVE Correction for “The sui generis Sydney Brenner,” by Thoru Pederson, which was first published June 10, 2019; 10.1073/ pnas.1907536116 (Proc. Natl. Acad. Sci. U.S.A. 116,13155–13157). The author notes that, on page 13155, left column, second paragraph, lines 13–14, “Cyril Hinshelwood at Oxford, a leading figure in the early bacteriophage field” has been revised to read “Cyril Hinshelwood at Oxford, a chemist turned bacteriologist.” Additionally, in the original version of this article, the author stated that the experiments performed by Brenner and Crick involved chemically induced mutations in given DNA letters. In fact, most of the data were from spontaneous mutations. We have removed this incorrect assertion. The online version of the article has been corrected. Published under the PNAS license. Published online July 15, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1910910116 CORRECTION www.pnas.org PNAS | July 23, 2019 | vol. 116 | no. 30 | 15307 Downloaded by guest on October 1, 2021 RETROSPECTIVE The sui generis Sydney Brenner RETROSPECTIVE Thoru Pedersona,1 Sydney Brenner died on April 5, 2019, at age 92. His fame arose from three domains in which he operated with uncommon intellectual vibrancy. First were his prescient ideas and breakthrough experiments that defined the DNA genetic code and how the informa- tion it contains is transmitted into proteins. Second, in a later career, he developed a model organism, the roundworm Caenorhabditis elegans, to determine how the cells of an animal descend, one by one, along pathways of increasing specialization. Last was his be- guiling skill as an intellectual sharpshooter, often sur- prising colleagues by the immediacy of his “take” of a problem, even ones somewhat beyond his ken. He always was very swift to the core point and instant with a wise reply. Even though most of Brenner’s career was about the gene, it is to be emphasized that he was a keen biologist from the start. As an undergraduate at the University of Witwatersrand, South Africa’s top univer- sity, he strayed from his premedical curriculum and became adept at looking at various protozoa and cul- turing them in the laboratory. He also got keen about meiosis and wrote a brief report in Nature on the high frequency of multipolar spindles, a biological oddity he found in the sperm of the South African jumping shrew, Elephantulus (1). Captivated by chromosomes Sydney Brenner, 1927–2019. Image courtesy of Science and genes at this early stage, he then read publica- Photo Library/James King-Holmes. tions of Cyril Hinshelwood at Oxford, a leading figure in the early bacteriophage field. Winning a scholarship because his forte was the method of X-ray diffraction to attend Oxford, it was with Hinshelwood that Bren- ner’s fascination with the gene was catalyzed into full of crystallized proteins, he also happened to be very action. There, he did important work on how phages tuned in to the ongoing work of James Watson and can go into transient dormancy. It seems likely that in Francis Crick in Cambridge. Dunitz took Brenner to doing these experiments, he came to perceive that Cambridge to see the double helix that Watson and DNA can be active or silent, a concept that had arisen Crick had come up with. This moment in Brenner’s elsewhere, but this was likely his first intimation. career has not always been adequately conveyed by Brenner might have continued working with bac- historians, but I believe it was huge. terial viruses, a field being revolutionized at the time Of course, that trip up to Cambridge had a second by the former physicist Max Delbruck, or he might impact that was also powerfully catalytic and endur- have gone back to his beloved protozoa. But some- thing else happened: A visitor arrived. ing: Sydney and Francis Crick met. Much has been A scientist named Jack Dunitz from Caltech came written about the intellectual intensity of their decades to Oxford. He was an expert on protein structure, and long resonance, and if I were to have one wish that an aDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605 Author contributions: T.P. wrote the paper. The author declares no conflict of interest. Published under the PNAS license. 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1907536116 PNAS Latest Articles | 1of3 angel could descend and offer me, it would be to have experiments had not really proven that the code has been a fly on the wall of the office that they shared. three letters, mentioning that it could be a hextet The double helix was done, but what next? One code or, in principle, one based on any factor of three. project involved Mahlon Hoagland, the codiscoverer The students like this too, and say things like “Wow, of transfer RNA, which Crick had predicted but they were very smart.” Brenner has left us so many thought might only need to be three nucleotides long things like this. (okay ...agenius can be off by ∼25 and get away with But, at this point, Brenner was not finished with the it). Transfer RNAs are small molecules that translate genetic code. In further studies, he confirmed that the DNA coding into protein by each one of them con- code was manifest as a collinearity between the gene necting to and bringing into the protein synthesis ma- and protein (4). But that still not was enough for his chine a particular amino acid, the building blocks of agile mind. He went on to discover three so-called protein, one by one. Hoagland and Crick worked away nonsense elements in the code that cause termination in an attic laboratory at the Molteno Institute in Cam- of protein synthesis and revealed how their undesir- bridge, grinding up rat livers to seek the enzymes that able action is offset (5). hook adenosine 5′-triphosphate–activated amino After all this, a mind as uncommon as Sydney acids onto transfer RNA. It was a complete bust. Syd- Brenner’s didn’t go into cruise control. Amazingly, at ney watched this and thought that the better ap- the very same time he was working with Crick on the proach was genetics. His observation of this was, I genetic code, he and collaborators codiscovered mes- think, again one of those activities outside his own senger RNA (6). This was another Sydney Brenner tour laboratory that he monitored with a keen eye, both de force. He sensed that infection of bacteria by a hopeful and skeptical. In this particular case, it fueled virus, known to result in a shutdown of the host cell’s his constitutional talent for “finding another way.” RNA synthesis, would afford an opportunity to thus In what is perhaps one of the most elegant series of “see” the virus-produced RNA. Under judiciously se- experiments ever conducted in molecular biology, lected experimental conditions, an RNA species in- and far more elegant as cerebral foreplay and design deed revealed itself and fulfilled all of the predicted than the discovery of the double helix, Brenner, properties of the long-sought “messenger” RNA. This working with Crick, discovered that the four letters in great experiment also benefited from Mathew Mesel- DNA—A, C, G, and T—are “read” in sets. They son at Caltech, and from Francois Jacob visiting there achieved this by using chemicals to induce mutations from Paris, France. But the record shows that Brenner in a given DNA letter, this having been developed by was the inspiration (7). Edwin Freese at Caltech with Seymour Benzer and By this time, Brenner had become a legend and then refined by Freese at Purdue. Brenner and Crick dozens of postdocs flooded into the Laboratory of observed how this affected the resulting protein Molecular Biology at the University of Cambridge. encoded by this gene. This hallowed hall of molecular biology is itself legend The astonishing power of this series of experiments (8), and Sydney made it so on the genetics side, while was boosted by the fact that Brenner had previously Max Perutz and John Kendrew did so in structural bi- conducted an analysis that convinced him that what- ology. Many of the American postdocs who came ever this genetic code was, the letters specifying each wanted to work on RNA (9), but, by the late 1960s, amino acid in a protein’s linear sequence could not be some of these visitors sensed that Sydney was onto to overlapping whatever number of letters were specify- something new and switched their projects. What ing one of the 20 amino acids (2). How did he get this? was it? He looked at the limited amino acid sequences then at The gene had been good to Brenner, and he had hand and astutely recognized that the frequency of been good to its understanding. But let us recall his the same two amino acids appearing consecutively beginnings. Biology qua biology. So, sometime was too low to be explained by an “overlapping around 1965, he began to turn back to these roots. code” in which, for example, the (then hypothetical) He was influenced by nearby colleagues like Lewis DNA letters AAA coding for lysine (this discovered Wolpert and Peter Lawrence, as well as Francis Crick, later) should give lysine-lysine whenever there are four all of whom were getting keen about the notion that A’s in a row in the DNA. From an epistemological embryonic development and cell differentiation might perspective, in this insight, Brenner had helped ad- be explained by chemical gradients. This was not a vance the concept that however it was achieved, there new idea, but Wolpert had a particular knack for stat- was something “colinear” between the sequence of ing the problem in modern terms and he and Brenner letters in DNA and those in the encoded protein, as seemed to resonate.