Interview: Professor Tom Evans
Tom Evans is Professor of Molecular Biology at Glasgow, a Fellow of the Royal College of Physicians, he is on the Editorial Board of Shock & Immunology. His research interests include sepsis, a serious bacterial infection that results in a stereotyped host response.
1. What is your area of research? How have in vitro approaches played a role in understanding the clinical situation?
My research is concerned with understanding the mechanisms underlying the body’s response to severe bacterial infection, a condition known as sepsis. This is a common clinical condition which, despite considerable advances in Intensive Care Medicine and the development of antibiotics, still has a poor outcome. A large amount of research into the basic cell and molecular biology of sepsis has allowed considerable advances into developing novel therapies for the treatment of this condition.
2. Can you describe what are the strengths and weaknesses of in vitro approaches to understanding sepsis?
Sepsis is a complex pathophysiological condition, involving a number of different mediators. The strengths of in vitro approaches are that they can simplify the analysis of this problem, and study one factor in isolation from others that might be involved. This reductionist approach is one of the most powerful aspects of molecular biology and has allowed the properties of a number of key mediators in sepsis to be studied in depth.
In vitro studies have shown what receptors these mediators use and how they affect host cellular mechanisms. Paradoxically, the strength of the reductionist approach is also a key weakness in using this method to understand how sepsis affects patients. Whole organisms behave in very different ways from single cells, and a mechanism that is important at a cellular level may not be relevant to the total response of the patient.
3. Do you think that there are particular problems with in vitro studies in sepsis research that could be solved with more funding?
Funding plays a key role in shaping the direction of research. Any scientist would tell you that his or her approach would be much more successful if they had more funding! Cutting edge research is an extremely costly business, and developing new models of disease takes time and effort. The UK does face a problem in the level of funding for research, which compared to other places is really very low. This means that funding is naturally targeted to those projects with a high degree of likelihood for success, rather than to more speculative projects, which may require development of enabling technology.
New models and methods to use in in vitro approaches to study sepsis are still in their infancy, and tend to be more difficult to persuade agencies to fund. Thus, any funding that was specifically targeted to this area is undoubtedly of use.
4. What are the problems with using animal experiments to understand and treat sepsis in humans?
Animal experiments have been used extensively in sepsis research. I believe that they have provided us with information to allow better treatments for sepsis in humans. They are not perfect, however, for a number of reasons. Firstly, there is considerable species variability in the response to sepsis. Thus, the physiological changes in a pig or a dog are not necessarily informative of the changes seen in humans. This is at least part of the reason why a number of therapies that seemed very promising in the treatment of sepsis in animals failed in clinical studies.
Modelling clinical sepsis in an animal model is difficult. Onset in humans can be insidious, and once developed, clinical interventions such as antibiotic treatment and fluid resuscitation modify the clinical course considerably. Animal models of sepsis tend to be classified as severe in terms of likely suffering, as they use live infections. Thus, there are important ethical considerations in the use of animals in such models.
5. What techniques or approaches hold greatest promise for replacing animal experiments in sepsis research?
The development of alternatives to animals in sepsis research is still very much in development. There are some promising areas of research. Firstly, cell biological approaches are becoming increasingly more sophisticated. Cells can be grown in three-dimensional cultures and made to differentiate into structures with some similarity to how cells are organised into tissues. Physiological studies can be performed on cell cultures, such as spontaneously beating cells from heart muscle. Interactions between cells can be studied using mixed cell cultures.
Secondly, studies of human genetic variability will also shed light on the mechanism of sepsis. Huge amounts of sequence data from human DNA has identified many sites of minor genetic variability in areas of the genome involved in the control of sepsis mediators. Correlation of these changes with outcome in patients suffering from sepsis will provide important information on potential novel targets of therapy in sepsis.
Finally, the ability to identify the total spectrum of proteins expressed in a given tissue – proteomics – will provide vital clues as to the pathophysiological changes of sepsis and allow more rational development of drugs for treatment. These approaches will not likely provide answers in the immediate future, but will lead to a gradual process of reduction, refinement and some replacement of animals in sepsis research.
Further reading
Langley C, Brock C et al (2005). Opportunities to replace the use of animals in sepsis research. The Report and recommendations of a Focus on Alternatives workshop. ATLA 33:641-648.