ERC FUNDED PROJECTS

The study of host-pathogen systems is of central importance to the control of infectious disease, but also provides unique opportunities to observe evolution in action. Many pathogen species have diversified under selection pressures from the host; conversely, genes that are important in host defence also exhibit high degrees of polymorphism. This proposal divides into two parts: (1) the evolution of pathogen diversity under host immune selection, and (2) the evolution of host diversity under pathogen selection. I have developed a body of theoretical work showing that discrete population structures can arise through immune selection rather than limitations on genetic exchange. The predictions of this framework concerning the structure and dynamics of antigenic, metabolic and virulence genes will be empirically tested using three different systems: the bacterial pathogen, Neisseira meningitidis, the influenza virus, and the malaria parasite, Plasmodium falciparum. The current theory will also be expanded and modified to address a number of outstanding questions such whether it can explain the occurrence of influenza pandemics. With regard to host diversity, we will be attempting to validate and extend a novel framework incoporating epistatic interactions between malaria-protective genetic disorders of haemoglobin to understand their intriguing geographical distribution and their mode of action against the malarial disease. We will also be exploring the potential of mechanisms that can organise pathogens into discrete strains to generate patterns among host genes responsible for pathogen recognition, such as the Major Histocompatibility Complex. The co-evolution of hosts and pathogens under immune selection thus forms the ultimate theme of this proposal.

1 670 632 €

Start date: 2011-06-01, End date: 2017-05-31

Biopharmaceutical proteins are typically produced in cultivated mammalian cells, a costly process with limited scalability. Thus products such as monoclonal antibodies are very expensive and often beyond the reach of the world’s poor. The problem is compounded by the fact that important strategies for preventing diseases such as HIV and rabies typically involve large doses of multiple antibodies and other virucidal proteins. Plants have emerged as alternative production platforms for biopharmaceutical proteins because they are less expensive, more scalable and potentially could be transferred to developing countries. Recently, the first products have reached the clinic, but many of them are follow-on products already manufactured in mammalian cells. Here, Prof Julian Ma (St George’s Hospital Medical School, London, UK) and Prof Dr Rainer Fischer (RWTH Aachen University, Germany) aim to develop innovative ways to use plants for the economical, safe and sustainable production of combinations of active pharmaceutical ingredients (APIs) based on recombinant proteins, thereby pushing the boundaries of what can be achieved in plants beyond current capabilities with fermenter-based systems. We will focus on the production of antibodies and lectins against HIV and rabies, with the aim of generating GMP-compliant microbicidal cocktails for evaluation in human trials. Key aspects of the project will include the production of APIs both individually and as combinations in plants, the development of technologies allowing the introduction of transgenes into pre-determined genomic loci, the use of click chemistry to optimize the production and stoichiometry of recombinant protein cocktails, the development of candidate products for both topical and parenteral administration and the development of downstream processing concepts that are transferrable to developing countries, such as minimal processing and processing trains based on pre-assembled disposable modules. We will complete one Phase I clinical trials, each testing a plant-derived product that advances the field in a significant way

3 488 863 €

Start date: 2011-08-01, End date: 2019-01-31

Sexual reproduction is one of the most fundamental of biological processes: (i) the creation of gametes, (ii) their fusion and (iii) the formation of a viable embryo are all shaped by a major evolutionary force: post-copulatory sexual selection comprising sperm competition and cryptic female choice. This project will make substantial advances in all three areas, using birds (mainly zebra finch) as model organisms. (i) Sperm size and shape: A major hypothesis for the enormous variation across species in the design of male gametes is that a trade-off exists between sperm size and number. We will test this, by estimating (for the first time) the energetic costs of making sperm. (ii) Sperm-female and sperm-egg interactions. We will establish, how sperm from different males interact within a female and will do this, uniquely, by using transgenic zebra finches whose sperm flagella are labelled with green fluorescent protein (GFP). This allows us to distinguish (in the oviduct and in ova) the sperm from GFP- and normal males and to visualise how they interact to generate last male sperm precedence. (iii) The genetic and environmental causes of embryo mortality. We will explore the environmental effects of temperature on embryo development and survival and consider the special case of brood parasites that expose their ova to elevated temperatures through ¿internal incubation¿. We will explore the genetic effects of DNA integrity, aneuploidy and compatibility on embryo survival. Together, these three interconnected strands will revolutionise the study of reproduction, answering the most outstanding questions in the field through a combination of novel techniques and novel hypotheses.

1 700 000 €

Start date: 2011-05-01, End date: 2017-04-30

Scholarly preoccupations and much of the available evidence have tended to emphasise the Islamic era as the historic time period when the Mediterranean seaboard was firmly and regularly connected with the Sub-Saharan zone across the Sahara. Recent research in southern Libya suggests that there was a significantly higher level of Trans-Saharan trade and contact in the pre-Islamic period than hitherto recognised. The existence of an early state, contemporary with the Roman Empire, in the Central Sahara can be demonstrated from the archaeological remains of the Garamantes of the Libyan region of Fazzan. Their technological sophistication in terms of irrigated agriculture, urban settlements, mastery of pyrotechnical processes and manufacturing achievements in textiles and beadmaking are all quite remarkable. It is already clear that their population comprised a mixture of Sub-Saharan and Mediterranean African types and there is indisputable evidence that they traded with both the Mediterranean and Sub-Saharan zones. This has profound implications for understanding the nature and effects of human contact in the Trans-Saharan zone. The grant is sought to allow the research programme in Fazzan to be taken to the next level of analysis, enabling explicit comparisons and contrasts to be drawn with contemporary societies to north and south of the Sahara. Key themes to be explored include trade, human migration, technological processes and transfers, urbanisation and state formation. Equally crucial, the chronological scope of the project will be extended into the Islamic period, in order to understand how things differed then from the earlier phases of Trans-Saharan contact.

2 420 593 €

Start date: 2011-07-01, End date: 2017-06-30