Using human tissue in medical research throws up a number of different challenges. In our third 2012 NC3Rs 3Rs Prize post, Professor Gareth Sanger from Queen Mary, University of London, discusses how tissue removed from the stomach and intestine can actually help overcome some of these challenges. Is this a viable alternative to using animals for gastrointestinal research? Professor Sanger’s research suggests it could be.
Professor Gareth Sanger receives his NC3Rs 3Rs Prize at this year’s Annual Science Review meeting
How do you study gastrointestinal functions without using animals and without giving experimental drugs to humans? The answer is to use the material removed during surgery on humans for bowel cancer and other disorders.
Not all the material is needed for subsequent medical examination and provided the patient, surgeon and pathologist agree, and provided absolutely nothing is done to compromise medical care, a research laboratory can then study a piece of that tissue. Often, just anatomy is studied. However, researchers now need to know what the living tissue can actually do. Enter the team of scientists, surgeons, theatre staff and pathologists who must work together quickly to get the necessary agreements and keep the precious tissue alive so its functions can be studied in greater detail.
Overcoming the human variable
This is a complex procedure and for many laboratories proves a barrier to carrying out human tissue research. However, for the scientist, the problems don’t end there. Patients are people. They are male or female. They have different ages. They have enjoyed a hedonistic lifestyle or abstained from many earthly pleasures. This means that when anyone claims that human tissue research is better than using laboratory animals, there is a counter-claim, which argues that animal research is more precise, with fewer variables. It doesn’t seem to matter that the mouse is highly inbred and that the relevance of the different strains to human functions are unknown – the science is simply better.
Our recent study, published in the British Journal of Pharmacology and highly commended by the NC3Rs 3Rs Prize 2012, addresses the problem of variability among human tissues.
Professor Sanger demonstrating his research to The Queen.
71 patients agreed to donate (we have since studied many more) and we carefully noted their ages, gender, disease and other variables, maintaining absolute anonymity. We also monitored how long it took before experiments began, following removal from the patient. Surprisingly, human stomach and intestine are remarkably resilient and with care, we found we could store the tissues overnight in the fridge and keep them alive. With this attention to detail, we could be sure that our data were not distorted or confounded by the many variables associated with being human. We were, therefore, beginning to approach the precision expected from animal studies.
We studied the actions of a gastrointestinal hormone called motilin. This is released during hunger to stimulate stomach movements and perhaps initiate the ‘rumbling stomach’ of hunger. Laboratory rats, mice and guinea-pigs don’t make motilin or respond to it – another reason for developing a capacity to use human tissues in research.
The importance for drug design
We showed that motilin greatly increased the activity of the nerves controlling gastric emptying and small intestinal movements (without affecting the large bowel), explaining how drugs which mimic the actions of motilin can treat patients with delayed gastric emptying. These include patients in intensive care who are tube-fed and need help to maintain good gastric emptying and recover more quickly, as well as those suffering from diabetes and other disorders. We also showed that the effect of motilin was short-lasting, whereas the action of a potential new medicine was long-lasting.
This is an important aspect of new drug design, and has yet to be predicted by experiments using single cells. The results also helped predict the drug doses needed to be administered to patients in subsequent clinical trials. So, by establishing a capacity to use large amounts of human gastrointestinal material, we could conduct good, reproducible science. This would completely avoid using animals, and show mechanism, drug- and gastrointestinal region-dependent actions of motilin, data that could only have been obtained by using living human material donated by patients.
Broad, J., Mukherjee, S., Samadi, M., Martin, J., Dukes, G., & Sanger, G. (2012). Regional- and agonist-dependent facilitation of human neurogastrointestinal functions by motilin receptor agonists British Journal of Pharmacology, 167 (4), 763-774 DOI: 10.1111/j.1476-5381.2012.02009.x