obituary Joseph F. Sambrook (1939–2019)

t is impossible to measure just how big time imposed a moratorium on the cloning an impact Joseph (Joe) Sambrook had on of genes suspected of having oncogenic Ithe field of molecular biology. For almost potential! CSHL lacked the requisite 40 years, well-loved, dog-eared copies of his containment facility for such studies, so influential Molecular Cloning: A Laboratory a determined Sambrook would make Manual have been permanent fixtures in frequent expeditions to London’s Imperial nearly every biology laboratory around the Cancer Research Fund (now part of Cancer world. Colloquially known as the ‘cloning Research UK), which had agreed to make its Bible’, its study has been a rite of passage for containment facility available to him. many researchers. Sambrook’s other achievements during Sambrook was a true pioneer in a his time at CSHL include the first use of golden era of molecular biology. A proud restriction-enzyme polymorphisms as Scouser, he completed his Bachelor of genetic markers, elucidating the mechanisms Science degree with first-class honors in by which SV40 and adenoviruses integrate 1962 at the in the into the genome, and deciphering the UK. As circumstance would have it, the patterns of transcription and post- distinguished Australian virologist Frank transcriptional processing of mRNA. He was Fenner had at the same time embarked on also the first to develop and exploit the value a UK lecture tour during which he would Joe Sambrook at the Peter MacCallum Cancer of using ethidium bromide to stain agarose encounter Sambrook on a visit to Liverpool. Centre, East Melbourne, Australia (2009). gels containing DNA fragments generated by Sambrook, who even at a young age was Credit: Lynton Crabb Photography cleavage with newly discovered restriction unintimidated by status, asked a series of enzymes. challenging questions after Fenner’s lecture. It was also during his tenure at CSHL So impressed was Fenner that he offered that the seed was sown for the legendary Sambrook, then and there, a graduate PhD the minds of many, the study of animal Molecular Cloning manual. Sambrook, scholarship to join his laboratory at the viruses proven to oncogenically transform with colleagues Edward Fritsch and Tom Australian National University in Canberra. cultured animal cells. Renato Dulbecco Maniatis, had started a ‘how to clone’ This would prove to be the beginning of not had recently shown that simian virus 40 course to teach the basics of molecular only a stellar career that would span over 50 (SV40) malignantly transforms cultured biology to their visiting scientists. Sambrook years but also a lifelong affair with Australia, mammalian cells, work for which he would was a gifted and enthusiastic writer. He where he would come to live out his days. later be awarded a Nobel Prize. In 1967, commandeered in turn Maniatis, Fritsch, In his PhD thesis, titled The Genetics of Sambrook uprooted once again, this time David Russell and Michael Green to Animal Viruses, Sambrook isolated and to sunny California, to join Dulbecco produce, through four iterations, the characterized conditional lethal mutants, at the Salk Institute. As a junior fellow nucleic acid–centric instruction manual including temperature-sensitive and host- working in Dulbecco’s laboratory, Sambrook range mutants, of mammalian poxviruses. demonstrated that transformed cells carried After completing his PhD in 1966, several copies of SV40 DNA and, notably, Sambrook returned to England, where he that the viral DNA was integrated into the trained as a postdoctoral researcher with genome of the host cell. future Nobel Prize laureate Sydney Brenner At around that time, at the Medical Research Council Laboratory had taken over as Director of Cold Spring of Molecular Biology in Cambridge. Harbor Laboratory (CSHL) and was eager When he arrived, the genetic code had to expand its work to include mammalian been completely solved, except for one viruses. After a chance meeting at the Salk codon: UGA. Within just a couple of years, Institute, Watson recruited Sambrook to Sambrook had determined that the function CSHL to establish a tumor virus group. It of UGA in Escherichia coli is in fact not to was here that Sambrook really started to encode an amino acid; instead, it serves as a make his mark, and he would later quip chain-terminating codon. With his findings that he was recruited for 3 years and stayed published in Nature in 1967, the genetic for 16! Between 1969 and 1985, Sambrook’s code was finally complete, which helped to group grew steadily in size, eventually put Sambrook well and truly on the map as consisting of 60 scientists who were a major one of the most promising young molecular force in the study of tumor-associated viral biologists of the time. genetics. A primary goal of the tumour Sambrook started developing a keen virus group was the identification, mapping interest in the role that viral genes can play and analysis of the major genes of SV40 in human disease, including cancer. In the and adenoviruses. This was no small Joe Sambrook attending a Cold Spring Harbor late 1960s, the key to understanding the undertaking, especially given that the US Laboratory meeting, (1973). Credit: Photo courtesy molecular basis of human cancer was, in National Institutes of Health had at the of Cold Spring Harbor Laboratory Archives

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In 1985, with his wife-to-be Mary-Jane 2015, a multi-year, large-scale program, Gething (also a renowned senior scientist), funded by The Government of Victoria, on Sambrook was recruited to the University the personalized treatment of cancer. of Texas Southwestern Medical Center at Among his many honors, Sambrook Dallas: he, as Chairman of Biochemistry, was an elected Fellow of The Royal Society and Gething, as its first Howard Hughes (1985), an elected Fellow of the Australian Medical Institute Investigator. Building Academy of Science (1999), a Peter Mac on work started while Gething was still Distinguished Fellow in Cancer Research at the Imperial Cancer Research Fund in and the recipient of honorary doctorates London, and continued at CSHL, Sambrook from the University of Liverpool and the and Gething used viral vectors to express Watson School of Biological Sciences cloned influenza virus hemagglutinin and at CSHL. other membrane glycoproteins, which However, Sambrook’s legacy extends far would lead to important contributions to beyond his own personal achievements. the understanding of intracellular traffic Not only was he a giant in the field of and protein folding. They also devised molecular biology, but also he and his wife and patented a range of mutants of the and long-time collaborator Gething were Joe Sambrook in his laboratory at Cold Spring thrombolytic agent tPA (tissue plasminogen true trailblazers in their characterization Harbor, (1974). Credit: Photo courtesy of Cold activator), which they had cloned while at of molecular chaperones and the unfolded Spring Harbor Laboratory Archives CSHL. These mutants were better tolerated protein response, studies that formed the by patients and offered enhanced clinical foundation for a whole new field of biology. benefit relative to that of wild-type tPA; Sambrook took great pride in seeing those Molecular Cloning. These volumes served this led to the design and synthesis of a he had mentored achieve international as a foundation stone for the growth of new generation of tissue-type plasminogen recognition, and those who worked with CSHL Press and remain to this day the most activators that are still in clinical use today. him feel very privileged to have been part of popular and influential laboratory manuals In 1991, Sambrook became Director of his exceptional life. ever produced. the Eugene McDermott Center for Human After a long illness, Joe died peacefully In 1977, Sambrook was appointed Growth and Development at the University at home on 14 June 2019, with Gething and Assistant Director of CSHL. Sambrook’s of Texas Southwestern Medical Center, their daughter Honor at his side. He also personal style of leadership was renowned, before he was recruited back to Australia leaves behind three children from his first as was his increasingly formidable scientific in late 1994 to join the Peter MacCallum marriage, to Thelma, eight grandchildren reputation. He was fiercely combative with Cancer Centre (‘Peter Mac’) in Melbourne, and countless scientists who were blessed anyone prepared to engage in intellectual as Director of Research. In just 5 short years, by the aura of this giant of molecular jousting. His nose-to-nose style could be Sambrook completely revolutionized the biology. quite confrontational and intimidating, research enterprise at Peter Mac, instituting Consistent with his lifelong love of particularly to newcomers, although at heart an unflinching requirement for research music, Sambrook, along with Gething, everyone suspected it was good-natured excellence and a culture of collegiality established the ongoing Joseph Sambrook and just ‘Joe being Joe’! Indeed, behind his that permeated the organization. Through Opera Scholarship program using some sometimes harsh bark was an unquestionable astute recruitment, he almost tripled Peter of their royalties from the sales of tPA. On intent to help others. Always generous with Mac’s laboratory research workforce, from 14 July 2019, two of the recipients of the his time, Sambrook would give intense 75 to over 200, and set in place a research scholarships sang at a ‘Concert for Joe’, a thought to a researcher’s work and provide direction and strategy that grew in size, fitting send-off in lieu of the traditional valuable updates and encouragement to keep scope and impact under his dynamic funeral that he expressly did not want. ❐ going. He did this with good humor and a direction. Sambrook founded and directed twinkle in his eye, as he loved to surprise. the Kathleen Cunningham Consortium Ashley Dunn1, Ricky W. Johnstone2 and Sambrook taught his post-doctoral fellows for Research into Familial Breast Cancer, Bruce Stillman 3* to immerse themselves in their projects, to the first ever clinical cohort of its kind. 1University of Melbourne, Parkville, Victoria, avoid the trap of following the pack and to It brought together experts from across Australia. 2Peter MacCallum Cancer Centre, believe in themselves. Such was his impact clinical streams who work together to create Melbourne, Victoria, Australia. 3Cold Spring Harbor at CSHL that when he left in 1985, a newly a resource to solve pressing clinical, genetic Laboratory, Cold Spring Harbor, New York, NY, USA. constructed research building was named and epidemiological problems of familial *e-mail: [email protected] The Joseph F. Sambrook Laboratory in breast and ovarian cancer, a project that he appreciation of his contributions to was deeply passionate about. He was also Published online: 23 September 2019 the institution. one of two founding directors of Cancer https://doi.org/10.1038/s41594-019-0311-1

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