Professor John Harwood
Past and current research in my laboratory is focussed on the metabolism and function of acyl lipids. This work has involved elucidating new metabolic pathways, isolating and studying important enzymes and delineating regulatory mechanisms. For the latter, we have pioneered the application of flux control analysis to lipid biosynthesis.
Research is concentrated in three main areas. First, we have studied the effect of environmental stresses on lipid metabolism. Second, we have examined the biosynthesis of different plant lipids and regulatory mechanisms. This work has included both membrane and storage lipids and their constituent fatty acids. A third area concerns medical complaints where lipids play a key role. Arthritis, cardiovascular disease and dementia are the three main foci.
Metabolism and Function of Acyl Lipids
Environmental stress and lipid metabolism
Research includes a wide range of environmental factors and target organisms ranging from microbes to higher plants.
The Greenhouse Effect (raised atmospheric CO2 and temperature) has been found to change lipid metabolism, in keeping with its action in stimulating membrane biogenesis and growth. The alterations in metabolism can be explained by changed expression of two key enzymes which is now being tested directly. Linked to this work are experiments on temperature adaptation in the important soil protozoon, Acathamoeba castellanii. Low temperature effects have been separated from oxygen effects in inducing expression of n-6 fatty acid desaturase which renders the membrane lipids more 'fluid' and permits phagocytosis, which would otherwise stop at low temperatures.
Plant growth regulators, such as auxins, stimulate membrane lipid biosynthesis in peas and we have studied the control of phosphatidylcholine formation. An important control point is at the level of cytidylyltransferase and we have studied its regulation as well as isolating its gene. More recently, we have isolated the gene for choline kinase and purified and studied the enzyme. Another important plant membrane constituent is the sulpholipid. We have elucidated both its biosynthetic pathway and its degradation. The latter is important for sulphur re-cycling that has to take place each autumn (Fall) as leaves are degraded. The process involves a pseudo-glycolytic pathway using soil bacteria.
Several classes of pesticides act through their influence on lipid metabolism. We have studied several fungicides which kill plant fungi (potato blight, mildew) and which appear to alter lipid metabolism. Long-standing studies are also involved with thiocarbamates (a herbicide class that is effective through inhibition of fatty acid elongation and, hence, surface layer formation) and graminicides.
There is increasing interest in the toxic effects of heavy metals. We have shown that such metals interfere with lipid metabolism at various levels in marine algae, bryophytes and lichens. Some bryophytes are rather resistant to lead or copper challenge and may be developed for bioremediation. From brown algae, we have been able to isolate a metallothionein which is important for normal metal homeostasis.
Regulation of lipid synthesis in oil crops
Oil crops produce about 135 million tonne of product, worth around 115 billion US$ each year. In quantitative terms oil palm is the most important (about 25% total), soybean the second (22% total) and oilseed rape the third (13% total oil). There is a clear need to produce more oil, not only for edible uses but also as renewable chemical feedstocks. Moreover, understanding how quality is controlled is also important. We were the first lab to apply the technique of flux control analysis to lipid synthesis and have since used it to examine metabolic control in important crops such as oil palm, soybean, rapeseed and olive.
In oil palm the main control is exerted by the supply of fatty acids. Thus, efforts to increase yields of oil should be concentrated in oil palm lines which have higher rates of fatty acid synthesis. Although oil palm is 5 – 10 times as productive as other oil crops (on a per hectare basis), there is still the potential to increase its yields 2 – 3 fold. This would be of enormous benefit to the World.
Brassica napus (oilseed rape) is the main oil crop in Northern Europe and Canada. Most plantings use the low-erucate varieties which are suitable for edible oils. While studying the regulation of oil accumulation in B. napus we predicted that lines with elevated diacylglycerol acyltransferase (DGAT) would produce more oil. Transgenic lines with elevated DGAT activity have been shown to consistently produce 8% increased yields and to be more robust in drought conditions. We are now looking to see how further increases in yields can be obtained.
Lipid biochemistry and medical aspects
Several projects in the lab. are examining the role of acyl lipids in medical problems.
Pulmonary surfactant, which is continuously secreted into the alveoli, prevents lung collapse on breathing out (end- expiration). Premature babies do not make surfactant and, hence can suffer from respiratory distress. We were one of the first labs to design and test an artificial surfactant – such mixtures are so successful that they are used routinely nowadays. We went on to show how surfactant metabolism can be markedly influenced by dust (e.g. silica) inhalation and pin-pointed the molecular mechanism. A similar phospholipid-rich secretion is also formed in the peritoneal cavity where its efficiency is implicated in problems with renal dialysis and inflammatory reactions associated with surgical adhesions.
Inflammation also plays a role in endotoxic shock — an acute reaction by some patients to gram negative bacterial infections following surgery. We have found a correlation between the metabolism of polyunsaturated fatty acids in certain membrane lipids and pre-disposition to endotoxic shock. This discovery has been followed by the identification of specific acyltransferases which can mediate the changes in metabolism. One of these enzymes has been studied in detail and its gene identified. Interestingly, it shows changes in cell localisation during cytokine stimulation.
Arthritis is a widespread disease causing much suffering and which is mediated through excessive and chronic inflammation. We have been studying the molecular mechanisms behind the relief provided by fish oil diets rich in n-3 polyunsaturated fatty acids (PUFA). Such acids (but not other types of unsaturated or saturated acids) are able to reduce expression of inflammatory cytokines and eicosanoids and activity of cartilage - degrading proteinases in bovine chondrocyte cultures. In addition, we are probing the signalling pathways which underpin the effects on transcription. We have extended these exciting results to clinical trials as well as demonstrations that dietary n-3 PUFAs are very effective in dog food, especially for breeds prone to arthritis. They are now used in many proprietary brands.
Other diseases which have chronic inflammation as an important underlying factor include cardiovascular disease (CVD) and dementia. For CVD, n-3 PUFAs can be shown to be of benefit to individuals at risk of heart disease. We have demonstrated that they reduce low-density lipoprotein uptake by macrophages and, therefore, could reduce foam cell formation. Another (dietary) PUFA of potential benefit is dihomogamma-linolenic acid (DGLA) which, although a n-6 PUFA, is converted to anti-inflammatory products and reduces inflammation in macrophages.
With increasing life expectancy, dementia is becoming more and more prevalent. Alzheimer's Disease (AD) accounts for about 70% of the total dementia cases and costs the U.K. over £25 billion per year. The inflammation associated with AD can be significantly reduced by dietary intervention (fish oil or n-3 PUFA). This leads to reduced beta-amyloid deposits and better cognitive behaviour. Interestingly, the increased brain docosahexaenate (DHA) is selective for the ethanolamine phosphoglycerides which have been implicated in AD.
Honours and Awards
|2016||Stephen S Chang Award (American Oil Chemists Society) for decisive accomplishments in research for the improvement or development of products related to lipids|
|2016||Morton Lecture Award (Biochem. Soc.)|
|2014||Awarded the Chevreul Medal (Soc. Francaise Etudes Lipides, SFEL)|
|2014||Elected a Fellow of the American Oil Chemists Society|
|2014||Appointed international member of OTKA (Hungary)|
|2013||Elected the 2013 Fellow of the Institute of Biocatalysis and Agricultural Biotechnology|
|2012||Invited to be Joint Editor-in-Chief of The Lipid Library (main on-line source of information about lipids)|
|2011||Elected Fellow of the Learned Society of Wales|
|2011||AOCS Supelco/Nicholas Pelick Research Award for original research in lipid chemistry|
|2010||Elected Honorary Member of the Hungarian Academy of Sciences|
|2010||Elsevier Awards. Most downloaded articles in 2009 were Guschina and Harwood (2006) and Harwood and Guschina (2009), in their respective journals.|
|2006||Elsevier most cited paper award for work on new anti-malarials (Jones et al. 2004)|
|2002||Heritage Foundation Lecturer (Alberta, Canada)|
|2002, 2005, 2009||MPOB best publication awards for papers by Ph.D. student, Umi Ramli, on flux control. (Ramli et al., 2002a,b, 2005, 2009)|
|2001||Clare Curtis (Ph.D. student) received an AOCS Honoured Student Award|
|2000||AOCS Best Nutrition Paper Award (Salas et al.,1999)|
|1999||International Award (International Society for Fats and Oils ISF)|
|1998||Terry Galliard Medal for plant lipid biochemistry (ISPL)|
|1998||Kunio Yagi Award (PIPAC)|
|1997||Royal Society Visiting Scientist, Russia|
|1994||Undergraduate Science Lecture, Imperial College London|
|1992||Special Botany Lecture, University of Bristol|
|1990||Phytochemistry Society of Europe Award for 'outstanding research in phytochemistry by a younger European scientist'|
|1986||British Council Visiting Scientist, Japan|
|1979||D.Sc. (University of Birmingham) 'Metabolism and function of acyl lipids'|
Recent work in the lab. has been funded by the EPSRC, NERC, BBSRC, The Wellcome Trust, The Alzheimer's Research Trust and the EC.
It has also been supported by industrial collaborations with AgrEvo, Arcadia, DSM, DuPont, Johnson and Johnson, MPOB, Obsidian, Rhône-Poulenc and Syngenta.
Current collaborations (external)
- Kent Chapman (University of North Texas)
- Mee-Len Chye (Hong Kong University)
- Gary Dobson (Scottish Crop Research Inst., Dundee)
- Tony Fawcett (University of Durham)
- David Fell (Oxford Brooks University)
- Tony Kinney (DuPont, Wilmington)
- Enrique Martinez-Force (Instituto de la Grasa, Seville)
- Johnathan Napier (Rothamsted Research, Herts)
- Umi Ramli (Malaysian Palm Oil Board)
- Laszlo Vigh (Hungarian Academy of Sciences, Szeged)
- Markus Wenk (National University of Singapore)
- Randall Weselake (University of Alberta, Edmonton)