Microbial Genomics: Standing on the Shoulders of Giants

Professor Nigel Brown

In this autobiographical piece Professor Nigel Brown, outgoing President of the Microbiology Society, writes about inspirational teachers, pupils and researchers throughout his career. Professor Brown introduces his piece in our new video feature, where he discusses what a ‘giant’ means to him and how his research has been influenced by his peers.

Newton’s famous quotation in his 1676 letter to his arch-rival Robert Hooke is not original, but Newton was quoting the 12th Century cleric, Bernard of Chartres. This in itself has a message for modern science. It is perfectly possible for a relatively unknown individual to be quoted by a better-known, and often more senior figure, and for the quote, or even a scientific result, to be ascribed to the latter. That has certainly happened to me early on in my own career. However, some scholars believe that Newton’s motive in quoting Bernard of Chartres was much more pointed, as Hooke was of short stature and certainly not a giant in the physical sense.

So, which giants have been important in my career? It really started at secondary school with a biology teacher, Dennis Pallant. He was undertaking a part-time MSc by research while teaching us A-level Biology. The result was that from a class of 12 biologists at an ordinary grammar school, three of us ended up as research-focused professors. That was just one class – a number of other influential researchers were inspired in their careers by the same schoolteacher. The second significant influence at this time was Professor Eddie Dawes, a microbial biochemist at Hull, who persuaded me that the best biochemistry course in those days was at Leeds. My headmaster never spoke to me again after I left his Cambridge entrance preparation group.

After a good, but fairly normal, BSc and PhD training in Biochemistry I was awarded a Fellowship to work as a postdoc in Fred Sanger’s group at the MRC Laboratory of Molecular Biology, Cambridge. At the time César Milstein and Georges Kohler were doing the first experiments on monoclonal antibodies, Aaron Klug was pursuing his work on structural biology, John Walker had just started his work on ATP synthesis, John Gurdon continued his work on nuclear reprogramming, Sydney Brenner and John Sulston were working on C. elegans development, and in Fred Sanger’s group we had started to sequence DNA instead of RNA. During this time, I worked closely with Michael Smith, a Canadian visitor, who developed site-directed mutagenesis while he was with us. All of these individuals subsequently received Nobel Prizes for their work. The environment in which these giants lived and worked – I guess you might call it 'Brobdingnad' – was very formative in my early independent research career, as it was in the careers of many others. I learned to concentrate on the experiments and what they tell you and develop the appropriate tools to answer the questions you need.

The Brown group at the University of Bristol in early 1987, working on metal resistance, transposition and restriction enzymes. There is one future FRS in this picture.

My work on DNA sequence of φX174 got me my first job in the Biochemistry Department at the University of Bristol. From then on, my students and postdocs were a great influence on what I achieved, and I hope that I was a significant influence on them. At Bristol serendipity played an important role. My tool development work (mainly the search for and characterisation of new restriction enzymes) continued, but my first independent project lost out to a group in the US that was already well-established. So, I had to look for another project. Vilma Stanisich, working in Mark Richmond’s group, had discovered a mercury-resistance transposon and it had been shown that mercuric ions were detoxified by reduction to elemental mercury. Biochemically this was an interesting transformation, and I decided to sequence the transposon to determine the mechanisms both of transposition and of mercuric ion detoxification. Of course, such activities are not the purview of a single group and working with others on different systems we established the mechanisms of both transposition and mercury resistance, and additionally determined the mechanism of control of expression of mercury resistance genes. The giants in the mercury story included the chemists in Chris Walsh’s group, then at MIT, and the groups of Anne Summers at the University of Georgia, and Simon Silver, then at Washington University, St Louis. Another great influence was the opportunity offered by the award of a Royal Society EPA Cephalosporin Senior Research Fellowship, allowing me to concentrate on research and reduce my teaching load. Although we had no direct contact, other than an exchange of letters, Professor EP Abraham’s work and his patents on cephalosporin generated the funding for my Fellowship.

Interest in metal resistance led me to study copper resistance, lead resistance and zinc resistance in bacteria, together with forays into other work on Streptomyces and even work on the microbiology of the ambient air. David Hopwood’s group at the John Innes Centre was crucial in teaching me how to work with Streptomyces. During this period I moved from Bristol to a chair in Microbiology at Birmingham. Here for the first time, I had responsibility for managing other scientists in addition to managing my own team. Again, there were some giants who helped me to see further by their determination to see their own vision through. To stretch the analogy, I found that you can also learn from those who have limitations to their vision – by avoiding the mistakes that they make through inaction or poorly-explained strategies. Academic management comes down to “intentional influence”. This is something I tried to practice when Head of a School of Biological Sciences, and later as Head of Chemistry. Most academics like to think they are self-employed (but wish to draw a monthly salary) and, quite rightly, are not subject to the management levers that might be used in commerce or industry.

During this time, I was working on a number of Research Council committees, particularly for the BBSRC. Like many academics, I thought that the system could be improved and when the opportunity came, I applied for and was appointed to the position of Director of Science and Technology at the BBSRC. This was a fabulous job. Whereas in your own research team you can live vicariously on the achievements of your students and postdocs, at BBSRC I could live on the achievements of the whole UK research base. It was here that I came across my next giant - Julia Goodfellow, who was Chief Executive of BBSRC. Julia had superb management skills. She knew exactly what she wanted to achieve and made sure that you knew what your part was in achieving them. However, she was also very supportive, so the expectation to achieve was not threatening. I hope during that time my “intentional influence” was helpful in getting both Systems Biology and Bioenergy initiatives off the ground.

Part of my role at BBSRC was to bring to the Research Council some knowledge of how universities worked, as they were the major recipients of BBSRC grants. After a few years my knowledge was out of date, so when the head-hunters came round I was delighted to be appointed to the University of Edinburgh as Head of the College of Science and Engineering. Here I had oversight of seven departments – Biology, Chemistry, Physics and Astronomy, Geosciences, Informatics, Mathematics and Engineering. The management skills I had learned at Birmingham and BBSRC were required in spades to deal with the variety of disciplines I was responsible for there. I vividly remember that a request for a reference for a mathematician resulted in a letter of support containing a number of equations on which this candidate had worked. How was a microbiologist supposed to understand that? Subsequently, I became Senior Vice-Principal responsible for Planning, Resources and Research Policy, with academic oversight of an estate of more than 700 buildings, the research of 23 departments and a budget of £640 M per annum. Here the giants were not only the academic researchers and an excellent Principal, Sir Tim O’Shea, but also some very fine professional support staff with whom I worked. Often academics are dismissive of “the administration”, but without excellent professional staff universities would soon be in serious trouble.

I retired from the University of Edinburgh in 2012, almost coincident with my becoming President of the Microbiology Society (the Society for General Microbiology at the time). Of course, retirement is a misnomer – I consider myself not to be retired, just unsalaried! Certainly being President of such an active Society is a pleasure, albeit occasionally a demanding one. During the three years we have moved the Society’s offices to London, moved from two meetings a year to an Annual Conference and Focused Meetings, been more active in trying to influence national policy in line with our charitable objectives, bought a building in London with other societies, and changed both the Society’s logo and its name. There are other detailed changes too numerous to mention. This has only been possible with the support and hard work of colleagues on Council and excellent Society staff, who have been a pleasure to work with. I am honoured to have followed a number of giants of microbiology in being President of the largest and, in my view, the best microbiology society in Europe. Perhaps when I hand over the presidency to Neil Gow on 1 January 2016, my ever-supportive wife will have a partial answer to her question: “When is this retirement going to start?”.

In retrospect, my time at BBSRC and the University of Edinburgh were crucial in helping me to understand the political underpinning of research and research funding. At BBSRC I was working with the Departments of Environment, Food and Rural Affairs (Defra) and Business, Innovation and Skills (BIS) and, to a lesser extent, with HM Treasury ensuring that the importance of the research base was understood. Occasionally this could be difficult, such as during the 2007 foot-and-mouth outbreak, which emanated from the site shared by the BBSRC-sponsored Institute for Animal Health and Merial, a vaccine production company. At other times it could be amusing – such as when the Director General for Research and Innovation at BIS told us that Ministers were keen that BBSRC continued its Systems Biology Initiative as it was “perceived as changing the behaviour of biologists, and this was thought to be a good thing”!

In Scotland, the political dimensions were different. It was relatively easy to gain access to individual politicians and ensure that they understood the importance of research and teaching in the university system, and what science had to offer the economy. I sat on the Scottish Science Advisory Council, an independent body working with the Chief Scientific Advisor, and for a number of years we had the ear of the First Minister. More recently, however, the CSA’s position has remained unfilled and the SSAC has not met. There is a concern that political decisions relevant to science are being made without scientific advice.

Of course, no one person can fully understand the variety of disciplines present in a university, or required for truly cross-disciplinary research; and good teamwork is as essential in running an institution or an organisation as it is in running a research team. I have been fortunate that I have worked with people of clear vision and I hope that I have learned from them and been able to transmit a clear vision myself. Standing on the shoulders of giants is necessary not only to see further yourself, but also to point out the more distant landscape to your colleagues.

The Tn501 mercury resistance operon. Only the merRTPA structural genes are required for inducible resistance. merD encodes an additional requlator and merE an additional transport protein. The MerR protein represses both Pmer and PmerR in the absence of Hg(II), but represses PmerR and induces Pmer in its presence.

A schematic of mercury resistance in Gram-negative bacteria. MerP sequesters Hg(II) in the periplasmic compartment and transfers it to the inner membrane protein MerT, which then transfers it to the NADPH-dependent mercuric reductase. Hg(II) is reduced to elemental Hg(0), which can diffuse through the cytoplasmic and periplasmic membranes and volatilises from the environment of the bacterium.

Footnote: I have chosen not to give references to any of my work. My scientific publications can easily be found thorough common databases. Over the last decade, my few publications have often been on matters of research policy.

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