Martin Maiden's research

Understanding bacterial diseases: from genes to vaccines

As a sixth-form student in the late 1970s, I was inspired by a book entitled ‘The Natural History of Infectious Diseases’ by the great Australian microbiologist and immunologist MacFarlane Burnett.  This book presents disease in ecological perspective and was in many ways in advance of its time; however, whilst finding the subject fascinating, the book made me realise that a my future in biology would not be in studying infectious disease, as the orthodoxy of the time was that, in an age of antibiotics, vaccines, and malaria vector control with DDT, the infectious disease problem was solved.  The succeeding 30 years or so has seen the recrudescence of diseases once thought to be under control, such tuberculosis and malaria, and the emergence of many wholly new challenges, including HIV/AIDS, BSE (mad cow disease) and SARS. Infectious disease remains a crucial and vibrant research area and today there is an appreciation that this will remain the case for the foreseeable future.

My interest is in the bacteria that cause disease, particularly those that cause important diseases yet spend most of their time as harmless inhabitants of the human body, which is teeming with bacteria (at least ten bacteria for each human cell).  A case in point, and a major research focus of my research group, is Neisseria meningtidis, the meningococcus, which is notorious for causing frequently-fatal meningitis and septicaemia, but which is a common inhabitant of human throats – all of us will have lived intimately with these potential killers for most of our lives.  Perplexingly, as far as we can tell meningococcal disease is also a disaster for the bacterium, as the host on which it depends can be killed for no benefit to the bacterium – so why, and how, does a ‘friendly’ bacterium turn nasty?

The tools that we have available for studying infectious agents have undergone major changes in recent years, especially our capacity to read, or ‘sequence’ the complete genetic code, which represents the ‘instructions’ for making the bacterium.  In the case of the meningococcus, this comprises some 2.2 million bases, each one of four ‘letters’ that make up the genetic code.  However, although we can determine the sequence of letters and we understand the basic alphabet, we have only a rudimentary ability to ‘read’ this information and much remains to be learned.  In meningococcal research, however, encouraging progress has been made.  Together with colleagues around the world we have shown that relatively few of types of the meningococus are likely to cause disease, although meningococcal populations are bewilderingly diverse, with many different types that vary, at the genetic level, about as much from each other as humans do from mice.  This observation forms the basis of both our understanding of why the meningococcus causes disease and also helps us to develop strategies to prevent this happening, for example with new vaccines.  We are beginning to understand that the diversity of meningococci is driven by complex ecological interactions with the human host, leading to counterintuitive and paradoxical outcomes such as the emergence of more virulent types that may damage or kill the host.

There have been encouraging advances in combating meningococcal disease in the past 15 years, including the introduction of new vaccines that have controlled ‘Group C’ meningococcal disease in countries such as the UK, and ‘Group A’ disease in Africa.  We have played a role in establishing that the success of these vaccines is, in large part, due to ‘herd immunity’ against particular meningococci.  Herd immunity is the idea that if sufficient people are immunised appropriately, the bacterium can no longer spread, protecting the whole community, vaccinated and unvaccinated, from infection and therefore disease.  There remain major challenges in the development of an effective and comprehensive vaccine against Group B meningococci and other areas of our research, along with that on many colleagues, focus on how to immunise effectively against Group B bacteria.  If the research community can solve this problem then meningococcal disease may become a thing of the past.