Dr Florian Merkle
Dr Florian Merkle
Human stem cell models of obesity and neurological disease
Email: fm436@cam.ac.uk
Departmental Affiliation: Pharmacology
ORCID: 0000-0002-8513-2998
Biography
Florian Merkle obtained his bachelor degree in biology from Caltech and his PhD in Neuroscience at UCSF where he determined the lineage and potential of adult neural stem cells in the mouse brain. He then pioneered human pluripotent stem cell (hPSC) differentiation to hypothalamic neurons and was an early adopter of CRISPR/Cas9-gene editing in hPSCs as a postdoc at Harvard University before joining the Institute of Metabolic Science (IMS) at the University of Cambridge in 2015 as a New Blood fellow. At the IMS, Florian became a Sir Henry Dale Fellow, Ben Barres Fellow, and Robertson Stem Cell Investigator before joining the Department of Pharmacology in 2024 as an Associate Professor (Senior Lecturer). Florian’s contributions to the field have been cited over 10,000 times and published in leading journals including Nature, Science, Nature Genetics, and Cell Stem Cell. Florian is an affiliate member of the IMS and Cambridge Stem Cell institute, and serves as an industry consultant, board member, and entrepreneur. He has received numerous awards including a “Golden Ticket” (NovoNordisk), the Michael Harbuz Young Investigator Prize (British Society for Neuroendocrinology), C.J. Herrick award in Neuroanatomy (American Association of Anatomists), and a Springboard Award (Academy of Medical Science). In addition to helping train the next generation of leaders in his group, Florian mentors early career researchers across the UK, and helps organise a programme to give undergraduates from under-represented backgrounds the chance do life science research at Cambridge.
Plain English
Florian is interested in the cause and treatment of obesity, which is largely due to excess food intake. Food intake is regulated by neurons (brain cells) found in a region of the brain known as the hypothalamus. Hypothalamic neurons can be generated in a culture dish from human stem cells. The Merkle laboratory uses a combination of cutting-edge approaches to determine how human appetite-regulatory neurons respond to drugs like Ozempic, with the ultimate aim of discovering more effective treatments.
Research
The Merkle group uses a combination of human pluripotent stem cell (hPSC) and animal models to pursue three research areas with the ultimate aim of developing new therapies. First, they have studied genetic stability of hPSCs and are identifying culture methods that minimise the appearance of culture-acquired mutations such a TP53 point mutations. They helped identify KOLF2.1J as a ‘reference’ human iPSC line that is now used by over 750 groups in 28 countries worldwide and forms the basis of several large-scale studies. Second, the Merkle group differentiates hPSCs into hypothalamic neurons that regulate appetite and has used this model system to both reveal how anti-obesity drugs like semaglutide (Ozempic/Wegovy) signal, and to identify new candidate appetite-regulatory targets and anti-obesity therapeutic strategies. Third, they use hPSC and mouse models to study the neuroprotective effects of anti-obesity drugs and optimise therapeutic strategies, since drug repurposing offers a rapid path to the clinic. One drug identified using this strategy is likely to be included in a large-scale clinical trial in the near future.
Research interests
The Merkle laboratory studies the mechanistic basis of human neurological diseases using human pluripotent stem cell (hPSC)-derived cellular models and animal models in order to develop more effective treatments. Our interdisciplinary group uses a variety of techniques including CRISPR/Cas9-based genome engineering, single-cell transcriptomics, quantitative proteomics, high content imaging, and disease-relevant functional phenotyping at scale, such as multi-well calcium imaging. We collaborate widely with other academic groups and with industry partners such as NovoNordisk and AstraZeneca. Our research focuses on three main areas:
Technology development for hPSC-based disease modelling
To facilitate effective disease modelling and safe cell therapy based on hPSCs, we led efforts to sequence their whole genomes, revealing the presence of germline and somatic genetic variants that make some cell lines predisposed to display disease-relevant phenotypes (10.1016/j.stem.2022.01.011, 10.1016/j.stem.2022.11.006), and other cell lines likely unsuitable for cell transplantation due to the presence of dominant negative mutations in the tumour suppressor p53 (10.1038/nature22312). We are now systematically optimising hPSC culture conditions to improve genetic stability by reducing the selective advantages these acquired mutations confer. We helped leverage the genetic diversity present among hPSCs by pooling hundreds of cell lines together, differentiating these pools, and using single-cell RNA sequencing to reveal how common genetic variants affect differentiation potential and disease-relevant phenotypes (10.1038/s41588-021-00801-6). To facilitate reproducibility and data integration, we helped to deeply characterise and select a ‘reference’ iPSC line that has now been shared with over 750 groups in 28 countries (10.1016/j.stem.2022.11.004,10.1016/j.stem.2024.02.006). The resulting cell line, KOLF2.1J, now forms the basis of numerous large-scale gene editing initiatives and much of the work in our own group. Specifically, we worked with collaborators to identify genetic constructs that resist transgene silencing (10.1101/2025.04.07.647695) and used these to create stable a Cas9-expressing cell line to facilitate arrayed and pooled CRISPR screens. We also generated knock-in cell lines to facilitate cellular phenotyping at scale, including multi-well calcium imaging to measure the functional responses of hPSC-derived neurons to drugs, chemicals, and hormones.
Central mechanisms of obesity and anti-obesity drug discovery
Obesity affects over a billion people around the world and is a leading preventable cause of disability and death. Despite the revolutionary progress of new anti-obesity therapeutics such as Semaglutide (Ozempic/Wegovy), not everyone responds to these medications or is able to tolerate them, and there is a pressing need for new and more effective treatment strategies. We hypothesise that since obesity is a highly heritable disease of the brain, such therapeutic strategies will act on brain cell populations critically important for regulating food intake. Specifically, pro-opiomelanocortin (POMC) neurons of the arcuate nucleus of the hypothalamus secrete melanocyte stimulating hormone (MSH) peptides that inhibit appetite. The activity of POMC neurons is in turn activated by metabolically important hormones such insulin, leptin, and glucagon-like peptide-1 (GLP-1) that are secreted by pancreatic beta cells, adipocytes, and gut enteroendocrine cells (and some hindbrain neurons), respectively. Much of what we know about POMC neurons comes from studies in animal models, and to study human POMC neurons at scale the Merkle laboratory pioneered (10.1242/dev.117978) and refined (10.1002/cpz1.786, 10.1101/2023.07.18.549357) methods to generate them in large quantities hPSCs. We then showed that they closely resemble their counterparts in the human brain in the genes they express, the neuropeptides they produce and their responses to metabolites, hormones, and drugs (10.1101/2023.07.18.549357, 10.1016/j.molmet.2018.08.006), including semaglutide (10.1101/2024.04.02.587825). By characterising hPSC-derived POMC neurons, we found a drug targeting anaplastic lymphoma kinase (ALK) that potently suppresses food intake and reduces body weight in obese mice in vivo (10.1101/2023.07.18.549357). To discover other novel new treatment strategies, we developed scalable phenotyping approaches and knock-in cell lines to facilitate drug screens and CRISPR screens. We are also interested in the role of primary cilia, a hair-like sensory organelle projecting from most cells in the body, in metabolic sensing and appetite regulation, since defects in primary cilia are sufficient to cause obesity. To study primary cilia in human hypothalamic neurons, we developed new reporter cell lines (10.3390/cells13131156) and characterised ciliary proteomes to identify potential therapeutic targets (10.1101/2025.05.11.653368).
Shared mechanisms in metabolic and neurodegenerative disease
Mid-life obesity is a risk factor for dementia later in life, and caloric restriction, exercise, and certain anti-obesity and anti-diabetes drugs are neuroprotective, suggesting that shared mechanisms between metabolic and neurodegenerative disease. We are exploring these interactions using a combination of hPSC-derived cellular models and mouse models of proteinopathy (10.1101/2025.08.17.670564) with a particular emphasis on drug repurposing. Since it can take decades to develop new medications and there is an immediate clinical need, we hope to have a more immediate benefit to people suffering from neurodegenerative disease by repurposing drugs that known to be safe and effective when used in other indications. Using this approach, we found that the widely-used anti-diabetic drug metformin penetrates the blood-brain barrier, slows disease progression in mice, and reduces histopathological markers of ER stress and neuroinflammation (10.1101/2023.07.18.549549), supporting the inclusion of metformin in a large-scale clinical trial of people with Alzheimer’s Disease. Using machine learning-assisted interpretation of mouse behavioural data, we found that the anti-diabetic drug pioglitazone significantly increases the health-span of treated mice (10.1101/2024.08.30.610328). In addition to testing other candidate drugs, we are now extending these studies to hPSC-derived models to deconstruct and reduce the complexity found in the brain and reveal candidate neuroprotective mechanisms that could be targeted more effectively by other drugs.
CSCI collaborators