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Staff Profile

Professor Colin Harwood

Professor of Molecular Microbiology

Background

Roles and Responsibilities

Qualifications

Ph.D. Microbial Genetics, University of Leeds

B.Sc. Biological Sciences, University of London

Memberships

Honorary Member of the Microbiology Society

Royal Society of Biology (Fellow) 

I am a member of the Biosciences Institute, and my work contributes to the Molecular and Cellular Microbiology research theme.

Research


I am a member of the Biosciences Institute, and my work contributes to the Molecular and Cellular Microbiology research theme.

Research Interests

Microbial protein secretion

Microbial responses to environmental stress

Microbial gene expression and regulatory networks

Genomics and functional analysis of Bacillus species

Antibiotic resistance transfer and regulatory issues concerning antibiotic resistance

Host genome refactoring for the production of specific metabolites and proteins

Current Work

Optimisation of Bacillus subtilis for the secretion of heterologous and industrial proteins and enzymes

Therapeutic proteins (including those required for experimental purposes and clinical trials) are major products of biomanufacturing processes and considerable time and expense are expended to maximise the yield and quality of proteins produced in heterologous hosts. The production host of choice is the Gram-negative bacterium Escherichia coli for which many strains and expression systems have been developed. However, one size does not fit all: E. coli is not suitable for the production of many proteins, either because it is not able to carry out appropriate post-translational modifications (e.g. glycosylation) or because it does not facilitate their folding into a native (i.e. functional) configuration. The former can be overcome by use of more expensive eukaryotic host production systems, while the latter can often be overcome by secreting proteins from the cytoplasm. Secretion has three major potential advantages over intracellular accumulation: the secreted target protein is usually natively folded; yields can be as high or higher than that obtained from intracellular E. coli host/vector systems; there is a reduced requirement for expensive extraction and purification procedures, with reduced risks of contamination with host proteins and nucleic acids.

Although various microbial protein secretion systems have been developed, all currently have limitations that restrict their use and value as a tool for the Biomanufacturing industry. These systems include secretion into the periplasm of E. coli and subsequent selective release and purification; production in the yeast Pichia pastoris; production in Bacillus subtilis and close relatives. In all cases, the yields are relatively low compared with that of the intracellular E. coli systems (mg rather than g per litre).

Bacillus subtilis is widely used for the commercial production of industrial enzymes, particularly for the food and detergents’ industries. Its advantage is its capacity to secrete native Bacillus proteins into the culture medium at concentrations in excess of ten of grams per litre. However, experience with the use of this bacterium for the production of heterologous proteins has been mixed with, in most cases, generally low yields. The aim of this proposal is to exploit knowledge of the genomics and systems biology of B. subtilis to develop this bacterium as a host/vector system for the production of high quality heterologous proteins for clinical trials and for high-throughput X-ray crystallographic studies. The aim is not to replace E. coli as the primary host for heterologous protein production, but to expand the range of host/vector systems that are available for problematical proteins.

Response of Bacillus spp. to environmental and host stresses  

Bacterial evolution is driven by environmental stresses and the need to both survive and compete. For example, infectious disease is the culmination of a battle between the pathogen and its host. Central to the host’s innate defence mechanism are phagocytic cells; macrophages and dendritic cells. Phagocytes express a series of antibacterial factors, including reactive oxygen and nitrogen species, antibacterial peptides and enzymes. They can also impose increased acidification. In spite of these defence mechanisms, several clinically important pathogens can proliferate inside macrophages. The interaction between Bacillus anthracis and host macrophages is central to its pathogenesis. However, an understanding of the cellular and molecular interactions between B. anthracis and the immune system is far from complete. B. anthracis avoids and even breaches cells of the immune system: vegetative cells avoid macrophages by virtue of their possession of a poly-D-glutamic acid capsule, while engulfment of spores by alveolar macrophages and their subsequent efficient germination within the macrophage is an important component of its ability to cause infection. However, it is not clear if B. anthracis can multiply in macrophages. We have dissected the B. anthracis-macrophage relationship through a combination of cellular, genetic and molecular approaches in comparison with a related environmental bacterium, Bacillus subtilis.

Regulatory issues associated innate and acquired antibiotic resistance

I work with European companies and trade organisation to address the issue of antibiotic resistance associated with industrial organisms use for feed and food. A key issue is the identification of innate resistance genes, that tend to remain stably associated with their host organism, and resistance genes associated with mobile genetic elements (MGEs) that are responsible for the widespread spread of antibiotic resistance organisms in the environment. In recent years we have collaborated with colleagues in civil engineering to develop and monitor the transmission of antibiotic resistance genes in water treatment plants. 

Postgraduate Supervision

Yes

Esteem Indicators

Elected Honorary Member of the Microbiology Society

Former Treasurer, Council Member and Publications Officer of the Microbiology Society

Treasurer and Board Member of the Federation of European Microbiology Societies (FEMS)

Former Board Member and Chair of the Finance Strategy Committee of the European Federation of Biotechnology (EFB)

Former Coordinator of two EU FP6 Programme

Advisor to European and Japanese Industrial Biotechnology companies 

Funding

EPSRC

BBSRC

TSB/Innovate UK

European Commission

Industrial Relevance

Biomanufacturing and regulatory issues concerning antibiotic resistance and secondary metabolite synthesis

Patents

1.Harwood, C.R., Stephenson, K., Jørgensen, S.T., Jensen, C.L., and Kristensen, T. (1999) Improved prokaryotic expression of proteins. International Patent. PCT/GB98/01051

2.Harwood, C.R., Stephenson, K., Sarvas. M and Kontinen, V. (1999)

Protein secretion. International Patent PCT/GB99/02191

Teaching

Undergraduate Teaching

BGM1004 - Genetics

CMB3000 - Research Project 

Postgraduate Teaching

PhD students


Publications