Anthony (Tony) W. Linnane: A man of mitochondria and much more

Tony Linnane was a highly accomplished research leader in the Department of Biochemistry at Monash University in Melbourne, Australia. He is well known as a towering figure of Australian and international Biochemistry not only for his outstanding research on the biogenesis of mitochondria but also for his roles in the Australian Biochemical Society (ABS, later becoming ASBMB) and the International Union of Biochemistry (IUB, later becoming IUBMB). Born in Sydney on July 17, 1930, Linnane received his PhD at the University of Sydney in 1956, working under the supervision of Professor Jack Still. In the mid-1950s he was the first to isolate functional mitochondria from baker's yeast, Saccharomyces cerevisiae, an organism with which he made his most lasting and impressive achievements during a remarkable two decades of work during the 1960s and 1970s. His later work branched out into a series of mammalian biochemistry and molecular biology projects covering diverse areas. These projects, some of which were pursued after he left Monash in 1996, predominantly had a biomedical focus embodying a drive toward clinical trials and commercialization. He continued working well into his eighties (Fig. 1), virtually to the day of his passing on November 11, 2017. Emeritus Professor Anthony Linnane, 2017. On completion of his PhD, Linnane went to the lab of David E. Green at the Institute for Enzyme Research at the University of Wisconsin, USA. Linnane pursued work on preparations derived from beef heart mitochondria, called electron transport particles, containing portions of what became later known as the mitochondrial respiratory chain. In his two years at the “Enzyme Institute” Tony encountered many leading biochemists of the era, providing an inspirational experience for him. The vision of contributing to science at the highest level permeated Tony's life from that time on. Returning to the University of Sydney in 1959, as Lecturer, Tony decided not to compete directly with the mammalian mitochondrial “heavyweights” he had encountered in the US, but to use yeast as a model eukaryote that not only contained functional mitochondria but also readily generated mutants called “petites” that lacked respiratory function. He realized that the emerging studies on protein synthesis, informed by genetic studies in bacteria, could be applied to yeast to work out how mitochondria are formed. In 1962, Linnane moved to Monash (as Reader in Biochemistry, to be made Professor in 1965). There his seminal work took off as he and his colleagues set up a series of elegant studies that demonstrated a protein synthesizing system within mitochondria of yeast, which could be inhibited by antibacterial drugs such as chloramphenicol to generate a respiration-deficient phenotype resembling that of petite mutants. Linnane's studies supported the then controversial view that mitochondria had evolved from bacteria. Linnane and colleagues discovered a series of antibiotic resistance markers (that presumably affected mitochondrial ribosomes), which were inherited separately from nuclear genes. At the same time, Linnane used the property of Saccharomyces as a facultative anaerobe to generate cells with primitive (under-developed) mitochondria after anaerobic growth in fermentative mode yielding ethanol as a product of anaerobic glycolysis. Restoring oxygen enabled the cells to regenerate mitochondria with their full array of membranes and respiratory enzymes, thus allowing biochemical approaches to analyzing mitochondrial formation. In the relatively well-funded environment in Australian Universities of that period, Linnane built up a formidable array of technologies including biochemistry, genetics, enzymology, electron microscopy and later, molecular biology, to investigate “the biogenesis of mitochondria,” a descriptor used by Tony to “tag” his research. The years 1967 through to 1987 saw a remarkable series of 66 publications under this generic title (plus many more without a “biogenesis of mitochondria” label) on a wide range of topics. Through such broad multidisciplinary approaches, with a common integrated focus, the formation of the mitochondrial organelle and its membrane-associated enzyme complexes of the respiratory chain and ATP synthase was elucidated. The key understandings to emerge from Linnane's work were that this process takes place by co-operative contribution of two genetic systems (the chromosomes containing nuclear DNA and another multicopy organellar genome in the mitochondria, called mtDNA), and two separate ribosomal protein-synthesizing systems: one in the cytosol and one within mitochondria themselves. A major achievement of Linnane and colleagues at Monash was the construction of the first physical map of yeast mtDNA in the mid-1970s. The physical mapping of 10 protein-coding genes and two rRNA genes on the circular mitochondrial genome was performed by molecular genetic techniques, exploiting the unique properties of petite mutants as deletion mutants each retaining a particular portion of mtDNA. This elegant physical mapping of gene locations predated the use of restriction enzymes, whose widespread application came later. Work after this period at Monash began to focus on the mitochondrial ATP synthase. As part of these studies, a series of novel monoclonal antibodies were made, which were highly efficient in immunoprecipitating the undissociated ATP synthase complex. These new tools allowed a series of experiments on the structure and function of this enzyme complex to be carried out. Linnane's senior colleagues during this highly productive phase of his career at Monash University included Bruce Lukins, Phillip Nagley, and Sangkot Marzuki (Fig. 2). Senior colleagues in the early days of the Centre for Molecular Biology and Medicine at Monash University, 1986. From left: Sangkot Marzuki, Phillip Nagley, Tony Linnane, Bruce Lukins. Monash University Archives, IN467. For these major contributions to understanding the formation of mitochondria, Linnane was elected as Fellow of the Academy of Science (Canberra) in 1972 and Fellow of the Royal Society (London) in 1980. Thereafter, Linnane's efforts changed direction and broadened in the 1980s. Molecular biology and antibody technologies were already strengths in the Linnane group and he capitalized on these to move into the diversified areas of human interferon research and antibodies recognizing serum mucins in colorectal and other cancers. Linnane's lifelong interests in mitochondria and bioenergetics (particularly oxidation/reduction) were refocused on mammalian ageing. He placed much emphasis on coenzyme Q10 (CoQ10) a key component of the mitochondrial respiratory chain, which at the time had emerged in the public domain as a dietary supplement sold as complementary medicine. Linnane had much success in attracting funds from private foundations and benefactions, as well as commercial investment capital, to support this broad range of activities. Linnane founded the Centre for Molecular Biology and Medicine (CMBM) in 1983. The CMBM provided the funds and ambience to allow Tony and colleagues in the Centre to pursue productive research in the three areas mentioned above, as well as supporting the basic research of his close academic colleagues at Monash and other collaborators in clinical settings. Linnane had been Head of Department on several occasions during his career at Monash since the 1960s. Whilst Linnane was Director of CMBM, in 1991, he resumed the headship of the Department of Biochemistry. He led the process of departmental name change (eventually to become Biochemistry and Molecular Biology in 1996). But pressures within that Department, in some measure assisted by forces within the University, led to Linnane's relinquishing the departmental headship in 1994. However, the situation became even more strained after he stepped down as departmental head. Linnane left Monash in 1996 to relocate CMBM as an independent incorporated entity first at the Repatriation Hospital in Heidelberg and then later in its longer-term home in the Epworth Hospital in Richmond (both locations are suburbs of Melbourne). Linnane retired from Monash as Emeritus Professor of Biochemistry and Molecular Biology in recognition of his highly meritorious 34-year service to the University. Linnane was honoured with AM (Member of the Order of Australia) in 1995 and was awarded a Centenary Medal in 2001 (an award created by the Australian Government, on the centenary of Federation of Australia). He was elected as Fellow of the Australian Academy of Technological Sciences and Engineering in 1999. Linnane and his colleagues in the independent CMBM pursued the avenues of research and development work in bioenergetics and therapeutics aimed at treatment of chronic diseases particularly those of ageing, mostly with private investment funds and support from private foundations. His main scientific contributions after 1998 were to studies on mtDNA mutations in ageing (extending work already commenced in the 1990s at Monash), use of CoQ10 in ameliorating bioenergetically insufficient physiological or medical situations, and the theoretical aspects of oxidation–reduction biochemistry underpinning the use of agents such as CoQ10 or vitamin C (ascorbic acid). The CMBM labs at the Epworth Hospital closed in 2007. But a new phase in Linnane's work had already opened. From about 2000, Tony had been collaborating in the biopharmaceutical area with Luis Vitetta, a medical scientist then at Swinburne University, Melbourne. In 2007, Vitetta moved to the Centre for Integrative Clinical and Molecular Medicine at the University of Queensland (UQ) in Brisbane. Linnane was appointed an Honorary Professor at UQ in 2007 to perform consultative work with Vitetta at the Princess Alexandra Hospital in Brisbane. After Vitetta moved to Sydney in 2013 as Director of Medical Research at MedLab Clinical, Ltd., both he and Linnane became adjunct Professors in the School of Medicine at the University of Sydney from 2014 (Fig. 3). Linnane still lived in Melbourne, and his role as consultant and advisor allowed his participation in the organization of clinical trials both in Sydney and in Melbourne. Tony Linnane in deep conversation with Luis Vitetta (left) in Melbourne, 2015. Tony Linnane made many contributions to the Australian Biochemical Society (ABS), the forerunner to ASBMB. He was NSW State Representative to ABS 1959–1960, Secretary of ABS 1961–1966, and President of ABS 1974–1976. His main contribution as Secretary was to ensure an international presence at the annual ABS conferences through the bringing of at least one eminent international speaker, who would not only participate in the conference but who would also visit other locations in Australia. In this period, an arrangement was made with the Biochemical Society UK to sponsor one such prominent biochemist to come to Australia each year for the annual ABS conference. Linnane was awarded the Lemberg Medal of ABS in 1972, and he was made an Honorary member of ASBMB in 2005. As President of ABS in the mid-1970s, Tony worked hard to bring the first IUB Congress to the Southern Hemisphere, and his efforts resulted in the 12th IUB Congress being held in Perth WA, in 1982. This Congress brought many distinguished Biochemists to Australia that year. Some visiting speakers also participated in satellite meetings, including one at Monash and another on the Indian Pacific train from Sydney to Perth over 3–4 days! The Congress was unfortunately affected by political aspects (external to Linnane) that resulted in denial of entry visas to Russian delegates by the Australian Government of the day. This led to complications for the 11th Ordinary General Assembly of IUB, in which resolutions were voted by the delegates present in Perth (Part 1). To allow the Russian delegates to record their votes, Part 2 of the General Assembly took place 3 weeks later in Moscow (all this was ably managed by Bill Whelan, then IUB General Secretary). Tony became involved in regional as well as international organizations. Such involvement was encouraged by various Presidents of IUBMB, especially E.C. (Bill) Slater (the Netherlands, 1988–1991) and Kunio Yagi (Japan, 1994–1997). Tony greatly valued these friendships and these individuals, together with Brian Clark (Denmark, IUBMB President 2000–2003), had much influence on his professional and research life 1. Linnane was President of the Federation of Asian and Oceanian Biochemists (FAOB), during 1975–1977 (FAOB was later to become FAOBMB). He was Treasurer of IUBMB for 9 years between 1988 and 1997. He was a driving force for the IUBMB Conferences held in each of the two intervening years between the triennial IUBMB Congresses. These took place during the period 1992 to 2016, the first being held in Nagoya, Japan and the last in Vancouver, Canada. One such Conference was held in Melbourne as the OzBio2010 Conference, under the leadership of Nick Hoogenraad and Phillip Nagley. Linnane was founding Editor of the IUB-sponsored journal Biochemistry International, published by Academic Press (Sydney) and running it from his office at Monash from 1980 until he left in 1996 (and for a short time after that until 1998). The journal had changed its name to Biochemistry and Molecular Biology International (BAMBI) in 1993 and, after Linnane left the position of Editor in Chief, in 1999 morphed into IUBMB Life published later by Wiley (so continuing to the present day). Linnane was awarded the IUBMB Distinguished Service Award in 2000. Additionally, in 1990, he was made an Honorary Member of the American Society for Biochemistry and Molecular Biology (the other ASBMB). Tony was a determined man for all his adult life, ever conscious of the drive to succeed at whatever he turned his hand to in the professional sphere. He had a great interest in horse racing throughout his life. In the most recent decades he enjoyed many happy times with his family, often travelling overseas with his second wife Daryl and the children. Tony had enduring friendships with many colleagues in Australia and overseas and, as befits one with the “old school” approach, each year he would send out many handwritten Christmas and Seasons’ Greetings Cards to his friends. Sadly, no such cards were received in December 2017. I apologise to all those colleagues of Tony Linnane whose names could not be mentioned here due to space limitations. I am grateful for Dr William J. Whelan (University of Miami, USA) for information about the General Assembly of IUB held in 1982.

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