The FRAME Alternatives Laboratory
New approaches to human disease models
The FRAME Alternatives Laboratory (FAL) is concerned with the use of human cells for the production of models of human diseases. This approach, integrated with trials involving human patients, aims to produce cellular models of human metabolism, toxicity and disease that will prove to be more effective and physiologically relevant than animal or animal cell-based research.
The laboratory works closely with surgeons at the Queen’s Medical Centre, enabling it to use samples from patients. This is approved by the local NHS ethics committee. The use of actual human tissue samples makes the FAL’s work more effective and relevant in investigating human disease.
Current projects involve disease mechanisms in diabetes, obesity and liver problems associated with them.
Human metabolic intervention study
Humans are the ideal models to study human disease. Rodents do not get fat like humans so are not the most suitable species. Using this approach, the FAL is investigating how the genetic make-up of obese individuals affects their capacity to metabolise fat. The implications are wide-ranging as obesity is known to trigger other diseases and knowing the genes involved may help to find treatments. This is important element to combat obesity since, for successful weight loss, diets should be suited to the individual genetic make-up. It also opens up new possibilities for drug development by potentially drawing attention to new drug targets.
Europe has devised a set of regulations to protect humans and the environment from toxic chemicals (the REACH regulation).
To comply, industries have to gather information about each chemical and a vast increase in animal tests is predicted. The FAL is part of a team aiming to find out if liver cell gene expression can be used to measure and predict toxic effects. An in vitro method will save animals and should protect people from unnecessary risks.
Primary cells and immortal cell lines
Primary cells, cultured directly from the living organism, only go through a set number of replications. This short lifetime reduces the cells’ usefulness in the lab. With collaborators, the FAL is developing a method for preserving human liver cells that will provide more opportunities to carry out in vitro (test tube) research on liver disorders. The FAL is also creating immortal cell lines from various human tissues such as liver, muscle and aorta, that are able to grow indefinitely and replace animal cells in tests.
Liver disease model
Non-alcoholic fatty liver disease may affect 20-30% of the westernised population and the most severe cases will progress to cirrhosis. Currently, there are no adequate in vitro human models and rodents are commonly used. The FAL relies on human volunteers and cells to study liver disease. Such human-based in vivo and in vitro experiments will improve understanding of the causes behind fatty liver disease. With this knowledge, it may be possible to prevent and find treatment for this disease.
Muscle cell model
Research into metabolic disorders has traditionally relied on hamster models. However, metabolism varies between species and the data may not be valid for humans. Therefore, some conditions, such as obesity and diabetes, should be studied in human models and, with that in mind, the FAL is trying to establish in vitro human muscle cell models for the study of metabolic diseases.
When it was first launched, the FAL concentrated mainly on replacements for acute toxicology testing such as the notorious LD50 test and the Draize eye irritancy test in rabbits. Over the years it has gained international recognition and many of its findings have been accepted in main-stream research. A number of replacement methods developed there are now in common use, contributing to a reduction in the number of animals used for toxicology testing.
The lab is based at the University of Nottingham Medical School. FRAME has had close ties with the University since the 1980s and, in 1991, a dedicated laboratory was established there. It began life as an allocated corner of the University's tissue culture suite but has grown steadily since then.
It is now a purpose-built, separate facility, fitted with ultra-modern equipment that supports its cutting-edge research. In 2005 it was relaunched following a total refurbishment, funded largely by a legacy from one of FRAME's long-term supporters, Julia Girling.
Laboratory research within the FRAME research programme has previously focused on the following areas:
- International alternative method validation studies.
- Development of cytotoxicity assays as replacements for acute toxicity tests such as the kenacid blue test.
- Development of replacements for the Draize eye irritancy test. The FRAME neutral red release assay is now available as a kit - Predisafe - marketed by Biopredic (France). The fluorescein leakage assay is used to model the barrier function of the eye.
- Development of a 3D human skin model for irritancy testing. The model is also being used to investigate the way in which parasites penetrate human skin.
- Development of models to investigate the effects of chemicals on the respiratory tract.
- Development of an assay to predict phototoxicity.
- Development of methods for embryotoxicity screening, using embryonic stem cell lines.