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The FRAME Laboratory was established at the University of Nottingham Medical School in 1991 and was the first UK lab fully dedicated to non-animal biomedical research. Today the FRAME Laboratory remains a centre of excellence for developing, modelling, and promoting the benefits of human-based in vitro approaches for research. Over the past 30 years, FRAME has provided funding to the lab to support the research projects being carried out by PhD researchers, post-doc students and undergraduates working and studying there. Currently, FRAME provides an annual grant of £200,000 to support the lab’s work. Our partnership with the University of Nottingham, and the FRAME lab, provides us with a unique opportunity to:
Under its first Director, Dr Richard Clothier, the lab focused primarily on developing toxicological testing for regulatory purposes to replace animal use in safety testing of cosmetics, chemicals, and drugs. During this period the lab formed many close collaborations with industry partners and helped develop and validate in vitro assays which were instrumental in providing the scientific basis which made possible the ban on animal testing in cosmetics. These tests include the Kenacid Blue Test as a replacement for the notorious LD50 test and tests for the prediction of eye irritancy based on the fluorescein. Tests that are commonly carried out on rabbits.
In line with FRAME’s mission, the lab is dedicated to not only conducting and sharing research that will help develop and showcase non-animal approaches but also to educate students and researchers in the lab, university and further afield on these approaches. Sharing not only the potential of human-based models but also good practice in vitro techniques, experimental design, and research ethics.
The lab accepts students whose projects are in line with its purpose. This FRAME funding helps directly support the projects, dissemination via publication and events, but also l allows the lab to ensure it has state-of-the-art equipment, and stability of support and expertise from the core staff, whilst at the same time maximising its impact by supporting the development of the next generation of non-animal researchers.
The running of the lab and supervision of projects and students working there is overseen and led by the current Director Dr Andrew Bennett, who was appointed in 2006. He is ably supported by lab technicians and post-doc researchers working within the lab.
Under Dr Bennett work at the lab has focused on developing human-based in vitro models to replace the need to use animals and animal cells in basic and applied disease research. This reflects the increasing trend for using genetically altered mice for human disease research and the high number of uses of animals seen in basic and applied research today.
You can contact Dr Bennett directly at the University of Nottingham.
The key areas of focus at the lab today are:
The FRAME lab has for many years been cultivating excellence in the field of 3D in vitro liver models not only for the potential these models hold in removing the reliance on animals for drug development but also for the study of liver disease. Drug-induced liver injury causes one in three market withdrawals of new medicines due to adverse liver reactions. The Lab continues to work on a biologically relevant, in vitro model of the liver which responds as the organ would in the body. Using 3D scaffolds, flow of nutrients and culturing expertise to grow human hepatocytes, Kupffer cells and stellate cells the lab continues to refine liver models that may one day directly replace animal use in toxicity tests.
Situated within the University of Nottingham Medical School the Lab has access to fresh liver tissue sourced via ethical approval. Whilst the primary cells obtained from this donated tissue provides the gold standard for human-based in vitro liver research, this donated tissue is a finite resource. Alongside work to improve and progress scaffolding and culturing methods to mimic the internal environment of the liver more accurately, the lab is also working on ways to produce sources of physiologically correct hepatocyte cells from hepatic progenitor cells which would increase sources of liver cells for in vitro research and reduce reliance on primary hepatocytes from donated tissue. Providing sources of biologically relevant cells for research is vital if these methods are to fully replace animal use. A lack of good quality human cells can limit or hamper in vitro studies and provide some researchers with justification for using animal cells, or worse carrying out studies on animals. Perfecting the culturing materials and protocols, encouraging tissue donation, and implementing supply chains for tissue is also key.
Over the past 30 years changes in diet and lifestyle have led to the development of a worldwide obesity crisis. In parallel with this increase in obesity, the incidence of non-alcoholic fatty liver disease (NAFLD) and subsequent non-alcoholic steatohepatitis (NASH) has reached epidemic proportions. Non-alcoholic fatty liver disease is where access fat has accumulated in the liver (steatosis) but not in relation to excessive alcohol consumption. There are often no symptoms associated with non-alcoholic fatty liver disease but is the commonest cause of abnormal liver blood tests in the UK and can lead to liver, heart and metabolic complications. Whilst in the initial stages of the disease may be harmless if it progresses the liver can become inflamed resulting in steatohepatitis. If inflammation becomes persistent this can cause scar tissue around the liver known as fibrosis, if this progresses it can result in cirrhosis of the liver and ultimately liver failure.
The global prevalence of non-alcoholic fatty liver disease is estimated by NICE to be 24%. There is currently a lack of effective pharmacological treatments for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, the most common approach is lifestyle modification through diet and exercise. In 2020 18,678 scientific procedures were carried out on animals for the purpose of basic research into the gastrointestinal system, including the liver. Just under 3000 more procedures were carried out for specific research into human gastrointestinal disorders including the liver.
One of the main problems encountered when attempting to develop new therapies for non-alcoholic steatohepatitis is the lack of a relevant experimental model with which to test them. Animal models – either through genetic, nutritional or chemically induced or a combination of these are capable of reproducing some of the hallmarks of non-alcoholic steatohepatitis. However, due to the crucial difference between human and rodent liver metabolism and the artificial nature of the dietary and genetic manipulation of the animals such models are inadequate for testing for either drug efficacy or safety.
Various projects in the FRAME lab have developed and implemented in vitro techniques using primary liver cells to study the progression and cause of non-alcoholic fatty liver disease and explore potential targets for future treatment of the disease:
PhD Student Sadiya Rahman‘s research focuses on new drug targets as a treatment for liver fibrosis using human liver (stellate) cells.
One of the main research areas the FRAME Lab is currently looking at is the effects of obesity and exercise on skeletal muscle tissue to help understand causes, and therefore possible treatments and prevention strategies for Type II diabetes.
In 2020 over 19,500 procedures were carried out on animals for basic research into the endocrine system and metabolism, a further 1,600 were carried out specifically to study human endocrine and metabolic disorders such as diabetes. 89% of these procedures were carried out on mice.
Whilst animals famously helped in the discovery of the hormone insulin and its role in treating diabetes, using laboratory animals to study type II diabetes today may not offer as much relevant insight into the condition as human-based research methods. Type II diabetes is a condition associated with ageing; however, most mouse-based research does not investigate age-related insulin resistance due to the time taken for the mice to develop the condition. Instead, to replicate aspects of type II diabetes in mice including risk factors such as obesity, scientists commonly use genetically altered animals, chemical or surgical intervention, and/or high-fat diets. All these methods have the potential to cause suffering to the animals used.
Researchers in the FRAME Laboratory have been using alternative in vitro approaches to investigate the effect of obesity on insulin resistance in muscle tissue. Other studies at the lab use volunteer patient data and tissue samples to study the effect of different carbohydrates on the metabolism of liver cells and taste preference due to action on the hypothalamus. You can read more about the science of the projects in the links below.
PhD student Andy Wilhelmsen used muscle tissue donated by volunteers to study the effect of obesity on insulin resistance by replicating the internal conditions muscle cells are exposed to in obese and non-obese individuals.
PhD Student Areej Alsolami, is using human muscle cells, donated by volunteers, to study the role of Lipocalin 2, a small protein produced and secreted from skeletal muscles in response to exercise, in metabolic syndrome. She is hoping that it may offer potential as a target for treatment in this range of conditions.
PhD Student Alan Heath, is using human liver cells to investigate the effects of normal dietary levels of fructose. He hopes to show that flattening the fructose spike after a meal reduces negative health effects and wants to identify natural dietary ingredients which help to achieve this.
The FRAME Laboratory has collaborated with neuroscientists for many years looking at neuroinflammation and inflammatory pain. In recent years the lab has started to explore the use of human-induced pluripotent stem cells to produce models containing neurones and microglial cells that will allow research into neuroinflammation and associated diseases without the use of animals.
In 2020 over 134,000 procedures were carried out on animals for research into the nervous system and just over 37.000 more for research into the human nervous system and mental disorders. Along with human infectious disorders (around 38,000 procedures), this is the disease research area with the most regulated procedures on animals recorded. Most of these animals were rats and mice. Read more on our latest statistics on animals in research page.
One such area where rodents are commonly used to model disease is for the study of Parkinson’s Disease. Humans are the only known species to suffer naturally from Parkinson’s, scientists, therefore, use neurotoxic chemicals and genetic manipulation to recreate physiological aspects of the condition. This creates scientific barriers due to species differences but rightly raises ethical questions, about the suffering caused to those animals and the scientific value of the research itself. Developing models that use human cells have the potential to provide more relevant information, which avoids animal use and may help shed light on diseases such as Alzheimer’s and Parkinson’s where our knowledge of the underlying mechanisms of the disease remains limited despite years of research using thousands of animals.
There is a need to establish reliable, ethical sources of human tissue to support the study of human disease in the laboratory (in vitro). Existing cell lines do not always behave in the same way as cells obtained directly from the body (primary cells). Scientists often therefore rely on animal tissue, which also may not behave in the same way. Induced pluripotent stem cells or ipscs, could potentially offer an endless supply of human cells for research, but they can be expensive and challenging to work with. These stem cells can be created from existing human cells such as blood or skin, once they have been reprogrammed back into stem cells they have the potential to become any type of body cell. This is a challenging process, but the FRAME Laboratory is demonstrating how these models can help inform our knowledge of disease and potential new treatments. The laboratory currently works with models of brain cells known as microglia. Microglia are the immune cells of the brain. Read more about the science of the projects in the links below.
PhD student Jade Edey‘s project aimed to generate and use human stem cells to create a microglia model to study the role of a specific protein linked to neuroinflammation.
PhD student Rawan Aloufi‘s project aims to generate a human model of microglia to study neuroinflammation in neurodegenerative disease research.
This is a list of recently published research papers involving the FRAME Laboratory which benefit from the annual FRAME grant.
A Comparison of Primary Human Hepatocytes and Hepatoma Cell Lines to Model the Effects of Fatty Acids, Fructose and Glucose on Liver Cell Lipid Accumulation Z.J Huggett, Smith A, De Vivo N, Gomez D, Jethwa P, Brameld J.M, Bennett A, Salter A.M. 21st December 2022 Nutrients 15 (1) 40 DOI:10.3390/nu15010040
Effects of Fatty Acids, Fructose and Glucose on the Accumulation of Lipid in Liver Cells: A Comparison of Primary Human Hepatocytes and Hepatoma Cell Lines Salter A.M, Huggett Z.J, Smith A, De Vivo N, Gomez D, Jethwa P, Brameld J.M, Bennett A. 30th November 2022 Preprints.org DOI:10.20944/preprints202211.0558.v1
M1 macrophages evoke an increase in polymeric immunoglobulin receptor (PIGR) expression in MDA-MB468 breast cancer cells through secretion of interleukin-1β Asanprakit W, Lobo D.N, Eremin O, Bennett A.J. 7th October 2022 Scientific Reports 12, Article No 16842 DOI:10.1038/s41598-022-20811-6
Integrins as a drug target in liver fibrosis Rahman S.R , Roper J.A , Grove J.I, Guruprasad P.A, Tao Pun K, Bennett A.J 20th January 2022 Liver International https://doi.org/10.1111/liv.15157
O9 M1 macrophages evoke an increase in PIGR expression in MDA-MB468 breast cancer cells through interlukin-1β Asanprakit W, Lobo D.N, Eremin O, Bennett A.J. 5th July 2021 British Journal of Surgery, Volume 108, Issue Supplement _5 https://doi.org/10.1093/bjs/znab282.014
O25 Expression of polymeric immunoglobulin receptor (PIGR) and the effect of PIGR overexpression on breast cancer cells Asanprakit W, Lobo D.N, Eremin O, Bennett A.J. 5th July 2021 British Journal of Surgery, Volume 108, Issue Supplement _5 https://doi.org/10.1093/bjs/znab282.030
O24 Predictive and prognostic roles of polymeric immunoglobuilin receptor in breast cancer Asanprakit W, Zaitoun A.M, Lobo D.N, Eremin O, Bennett A.J. 5th July 2021 British Journal of Surgery, Volume 108, Issue Supplement _5 https://doi.org/10.1093/bjs/znab282.029
Mixed Polymer and bioconjugate core/shell electrospun fibres for biphasic protein release. Adala I, Ramis J, Moussinga C.N, Janowski I, Amer M.H, Bennett, A.J, Alexander C and Rose F.R.A.J. May 2021 Journal of Materials Chemistry B 9(suppl 4) doi: 10.1039/D1TB00129A
Two weeks of early time-restricted feeding (eTRF) improves skeletal muscle insulin and anabolic sensitivity in healthy men Jones R, Pabla P, Mallison J, Nixon A, Taylor T, Bennett A and Tsintzas K. American Journal of Clinical Nutrition 2020. Volume 112, Issue 4, October 2020, Pages 1015–1028, https://doi.org/10.1093/ajcn/nqaa192
Comparison of primary human hepatocytes and HepG2 cells as models to study the development of hepatic steatosis Proceedings of The Nutrition Society 78(OCE1) 2019 Hugget Z, Brameld J M., Bennett AJ, Salter A.M.
Molecular expression patterns in the synovium and their association with advanced symptomatic knee osteoarthritis.Wyatt LA, Nwosu LN, Wilson D, Hill R, Spendlove I, Bennett AJ, Scammell BE, Walsh DA. Osteoarthritis Cartilage. 2019 Apr;27(4):667-675. doi: 10.1016/j.joca.2018.12.012. Epub 2018 Dec 28.
Postoperative inflammation and insulin resistance in relation to body composition, adiposity and carbohydrate treatment: A randomised controlled study. Tewari N, Awad S, Duška F, Williams JP, Bennett A, Macdonald IA, Lobo DN.Clin Nutr. 2019 Feb;38(1):204-212. doi: 10.1016/j.clnu.2018.01.032. Epub 2018 Feb 15.
n-3 polyunsaturated N-acylethanolamines are CB2 cannabinoid receptor-preferring endocannabinoids. Alharthi N, Christensen P, Hourani W, Ortori C, Barrett DA, Bennett AJ, Chapman V, Alexander SPH. Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Nov;1863(11):1433-1440. doi: 10.1016/j.bbalip.2018.08.003. Epub 2018 Aug 7.
Obese subcutaneous adipose tissue impairs human myogenesis, particularly in old skeletal muscle, via resistin-mediated activation of NFκB. O’Leary MF, Wallace GR, Davis ET, Murphy DP, Nicholson T, Bennett AJ, Tsintzas K, Jones SW. Sci Rep. 2018 Oct 18;8(1):15360. doi: 10.1038/s41598-018-33840-x.
IL-15 promotes human myogenesis and mitigates the detrimental effects of TNFα on myotube development.O’Leary MF, Wallace GR, Bennett AJ, Tsintzas K, Jones SW.Sci Rep. 2017 Oct 11;7(1):12997. doi: 10.1038/s41598-017-13479-w.
Effects of short-term energy restriction on liver lipid content and inflammatory status in severely obese adults: Results of a randomized controlled trial using 2 dietary approaches. Baldry EL, Aithal GP, Kaye P, Idris IR, Bennett A, Leeder PC, Macdonald IA.
Diabetes Obes Metab. 2017 Aug;19(8):1179-1183. doi: 10.1111/dom.12918. Epub 2017 Mar 31. Bioprinting Using Mechanically Robust Core-Shell Cell-Laden Hydrogel Strands Pritesh Mistry, Aied Ahmed Morgan, Alexander Bennett, Andrew Jing Yang Macromolecular Bioscience 2017 17(6):1600472 DOI10.1002/mabi.2016004720172.
Gene expression patterns in the synovium and their association with symptomatic knee osteoarthritis Wyatt, L.A, Mapp, P.I, Wilson, D., Hill, R., Scamell, B.E. Bennett, A.J. Walsh D.A.Osteoarthritis and Cartilage 2016 24(1):S28S29DOI:10.1016/j.joca.2016.01.078.
Effects of short term very low energy diets prior to bariatric surgery on liver histology and circulating biomarkers: Results of a Randomised Controlled Trial (RCT) Journal of Hepatology 2015 62(2):S716 DOI: 10.1016/S0168-8278(15)31187-9 Emma L Baldry, Guruprasad P Aithal, Philip Kay,e Iskandar Idris, Paul Leeder, Andrew Bennett, Ian Macdonald.
Effects of short-term energy restriction prior to bariatric surgery on liver fat, inflammation and systemic metabolic parameters. Diabetic Medicine 2015 32DOI: 10.1111/dme.2015.32.issue-S1 Emma L Baldry, Guruprasad P Aithal, Philip Kaye, Iskandar Idris, Paul Leeder, Andrew Bennett, Ian Macdonald.
Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation.Hassan S, Eldeeb K, Millns PJ, Bennett AJ, Alexander SP, Kendall DA. Br J Pharmacol. 2014 May;171(9):2426-39. doi: 10.1111/bph.12615.
Abnormal T regulatory cells (Tregs: FOXP3+, CTLA-4+), myeloid-derived suppressor cells (MDSCs: monocytic, granulocytic) and polarised T helper cell profiles (Th1, Th2, Th17) in women with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC) and surgery: failure of abolition of abnormal treg profile with treatment and correlation of treg levels with pathological response to NAC.Verma C, Eremin JM, Robins A, Bennett AJ, Cowley GP, El-Sheemy MA, Jibril JA, Eremin O. J Transl Med. 2013 Jan 15;11:16. doi: 10.1186/1479-5876-11-16.
The S349T mutation of SQSTM1 links Keap1/Nrf2 signalling to Paget’s disease of bone.Wright T, Rea SL, Goode A, Bennett AJ, Ratajczak T, Long JE, Searle MS, Goldring CE, Park BK, Copple IM, Layfield R. Bone. 2013 Feb;52(2):699-706. doi: 10.1016/j.bone.2012.10.023. Epub 2012 Oct 29.
Independent and combined effects of acute physiological hyperglycaemia and hyperinsulinaemia on metabolic gene expression in human skeletal muscle.Tsintzas K, Norton L, Chokkalingam K, Nizamani N, Cooper S, Stephens F, Billeter R, Bennett A. Clin Sci (Lond). 2013 Jun;124(11):675-84. doi: 10.1042/CS20120481.
Oleamide activates peroxisome proliferator-activated receptor gamma (PPARγ) in vitro.Dionisi M, Alexander SP, Bennett AJ.Lipids Health Dis. 2012 May 14;11:51. doi: 10.1186/1476-511X-11-51.
An in vitro model of chemotherapy-associated steatohepatitis: Induction of lipid accumulation in hepatocyte/non-parenchymal cell co-culture by 5-flourouracil and irinotecan Journal of the American College of Surgeons 2012 215(3):S26 DOI: 10.1016/j.jamcollsurg.2012.06.088 John S Hammond, Monika Owen, Elke Gottschalg, Nicola De Vivo, Guruprasad P Aithal Andrew Bennett, Dileep N Lobo.
Mechanistic randomised control trial of mesalazine in symptomatic diverticular disease 2012 Gut 61(Suppl 2):A51-A52 DOI: 10.1136/gutjnl-2012-302514a.119 Janette K Smith, David J Humes, Klara Garsad, Ching Lam, Andrew Bennett, John Scholefield, Abed Zaitoun, Robin Spiller.
Translation of New Technologies in Biomedicines: Shaping the Road from Basic Research to Drug Development and Clinical Application-and Back Again April 2012 DOI: 10.1002/9783527632909.ch6 Pharmaceutical Biotechnology Michael Balls, Andrew Bennett, David Kendall.
Visceral hypersensitivity in symptomatic diverticular disease and the role of neuropeptides and low grade inflammation. Humes DJ, Simpson J, Smith J, Sutton P, Zaitoun A, Bush D, Bennett A, Scholefield JH, Spiller RC. Neurogastroenterol Motil. 2012 Apr;24(4):318-e163. doi: 10.1111/j.1365-2982.2011.01863.x. Epub 2012 Jan 25.
Impaired uptake of serotonin by platelets from patients with irritable bowel syndrome correlates with duodenal immune activation. Foley S, Garsed K, Singh G, Duroudier NP, Swan C, Hall IP, Zaitoun A, Bennett A, Marsden C, Holmes G, Walls A, Spiller RC. Gastroenterology. 2011 May;140(5):1434-43.e1. doi: 10.1053/j.gastro.2011.01.052. Epub 2011 Mar 23.
Skeletal muscle metabolic gene expression is not affected by dichloroacetate-mediated modulation of substrate utilisation. Tisdale PB, Seevaratnam N, Macdonald IA, Tsintzas K, Bennett AJ. Ann Nutr Metab. 2011;58(1):19-24. doi: 10.1159/000322971. Epub 2011 Feb 8. Erratum in: Ann Nutr Metab. 2011;58(1):41.
The Use of Human Tissues and Cells in Biomedical Research: The Unusual Suspects 2010 Alternatives to laboratory animals: ATLA 38 Suppl 1:5-9 Andrew Bennett.
Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Scott DJ1, Devonshire AS, Adeleye YA, Schutte ME, Rodrigues MR, Wilkes TM, Sacco MG, Gribaldo L, Fabbri M, Coecke S, Whelan M, Skinner N, Bennett A, White A, Foy CA. Toxicology. 2011 Nov 28;290(1):50-8. doi: 10.1016/j.tox.2011.08.015. Epub 2011 Aug 19.
An interlaboratory study to evaluate the reproducibility of toxicogenomics datasets 2010 Toxicology Letters 196DOI: 10.1016/j.toxlet.2010.03.518 Laura Gribaldo, Daniel Scott, Alison Devonshire, Andrew Bennett.
Systems Biology in Alternatives: The Importance of Human-based Studies 2009 ATLA 37 Suppl 2:89-91 Andrew Bennett.
MOLECULAR MECHANISMS UNDERLYING THE EFFECT OF PIOGLITAZONE THERAPY IN NON-ALCOHOLIC STEATOHEPATITIS (NASH) 2009Journal of Hepatology 50 DOI: 10.1016/S0168-8278(09)60694-2 Abdul Rahim, Guruprasad P Aithal, Ian Macdonald, Andrew Bennett.
Increased Intraepithelial Lymphocytes and Mast Cells with Depressed Serotonin Transporter in Duodenal Biopsies and Platelets of Patients with IBS and Diarrhoea (IBS-D): Correlation with Bowel Frequency 2008 Gastroenterology 134(4) DOI: 10.1016/S0016-5085(08)60196-1 Stephen J. Foley Gulzar Singh Laurie Chi Kwong Lau Andrew F Walls Geoffrey K Holmes Andrew Bennett Charles Marsden Robin Spiller.
The effects of underfeeding on whole-body carbohydrate partitioning, thermogenesis and uncoupling protein 3 expression in human skeletal muscle. Seevaratnam N, Bennett AJ, Webber J, Macdonald IA. Diabetes Obes Metab. 2007 Sep;9(5):669-78.
Searching for the answer to irritable bowel syndrome in the colonic mucosa: SERTainty and unSERTainty.Spiller R, Bennett A. Gastroenterology. 2007 Jan;132(1):437-41.
Elevated serum alanine transaminase in patients with Type 1 or Type 2 diabetes December 2006QJM 99(12):871-6 DOI: 10.1093/qjmed/hcl116 J West, James Brousil, A Gazis, Lucina Jackson, Peter Mansell, Andrew Bennett, Guruprasad P Aithal.
Differential regulation of metabolic genes in skeletal muscle during starvation and refeeding in humans.Tsintzas K, Jewell K, Kamran M, Laithwaite D, Boonsong T, Littlewood J, Macdonald I, Bennett A. J Physiol. 2006 Aug 15;575(Pt 1):291-303. Epub 2006 Jun 8.