RESEARCH

Dr Lynch earned his DPhil (PhD) at the University of Oxford, where he focused on the field of epigenetics - studying how special proteins attachment attach to the DNA to control cell identity. After that, he continued his research at King’s College London, in the Center for Stem Cells and Regenerative Medicine. There, he used advanced DNA sequencing, single cell analysis and computer modeling to better understand how cells are controlled in the human skin and how this is disturbed in cancer.

Dr Lynch has published extensively on skin cancer, skin aging and artifical intelligence (AI). A focus of ongoing work is to understand the role of connective tissue cells "fibroblasts" in cancer, aging and scars. Fibroblasts are a type of cell found in connective tissue throughout the body, playing a crucial role in healing and tissue repair. They produce the extracellular matrix, providing structural support to the skin. Fibroblasts are active in wound healing, where they help to close wounds and rebuild damaged tissue. Additionally, they are involved in the maintenance of skin elasticity and firmness through the production of collagen, elastin, and other components.

An important finding is that fibroblasts can be subdivided into 4 different types 'subpopulations' each of which has a specific location within the skin. You can learn more about some key papers authored by Dr Lynch below.

This recently-published paper, on which Dr Lynch is senior author, describes the highest resolution map reported to date for cells in healthy skin and basal cell carcinoma (BCC) - the most common form of skin cancer.

This study used several complementary methods to look closely at skin cells and how they are organized in both healthy skin and BCC:-

1. Optical Coherence Tomography (OCT): This is a special imaging technique that generates very detailed pictures of the skin without having to cut into it. It helps them see the skin's structure and the blood vessels inside it.

2. Single-cell RNA sequencing (scRNAseq): This method examines the activity of genes in individual cells. By looking at which genes are turned on or off, it is possible to identify different types of cells and understand what each cell is doing.

3. Spatial Transcriptomics: This technique is used to map where in the skin different cells are located. It gives a big-picture view of how cells are organized and how they interact with each other in both healthy skin and BCC.

4. In Situ Sequencing: This is another way to look at gene activity, but it's done directly in the skin tissue samples allowing the identity of single cells to be seen in the tissue.

5. Computational Analysis: Complex computer programs were used to analyze and make sense of the information. This helped understand where different cell types are located and how they change in skin cancer.

This plot shows the results of the Single Cell RNA sequencing. The different coloured clusters represent different cell types within the skin including immune cells, blood vessel cells, fibroblasts (connective tissue cells) and keratinocytes which form the barrier layer of the skin. For some of the cell types, for example the fibroblasts, there are several clusters and this represents different subpopulations of cells.

Generally, the types of cells in healthy skin and BCC are similar. Interestingly, there was evidence suggesting that BCC arises from hair follicle cells, and they observed that cancer-associated fibroblasts (connective tissue cells that form part of the tumour) in BCC expand from a specific subgroup normally associated with hair follicles in healthy skin. You can see the results of in situ sequencing above with the expanded fibroblast population showed in green. These findings could help in understanding how BCC develops and in identifying new treatment targets.

This paper, published in 2018, for which Dr Lynch was joint senior author, describes one of the first single cell RNA sequencing studies of human skin. By comparing human and mouse skin closely, using advanced techniques to look at individual cells and how they function, it was shown that human skin has at least four different types of fibroblast cells.

In the lower left panel of this figure you can see the result of single cell RNA sequencing showing 4 different fibroblast populations in the dermis.

Skin cancer is caused by mutations in skin cells. In this study, published in 2017 for which Dr Lynch was the first author looks at how mutated cells in human skin compete and grow.

The skin gets damaged by sunlight, leading to mutations. By examining small pieces of skin from people of different ages, it was found that the growth of mutated cells is not random. Instead, mutated cells that have a competitive edge grow in specific patterns, influenced by their location and interactions with neighboring cells. Maths and computer simulations showed that both random growth and competition are important in determining which mutated cells end up spreading. This helps us understand how cancerous cells might develop and spread in the skin, depending on where they are and how they interact with other cells.

Epigenetics describes to the mechanisms by which cell identity is controlled in a tissue. This is important for healthy skin cells and is disturbed in skin cancer. It has also been shown that changes in epigenetic profiles are closely correlated with skin aging. This study, published in 2012 for which Dr Lynch was first author, focused on an important epigenetic mechanism known as Polycomb proteins.

By comparing human and mouse DNA regions it was found that certain areas attract the Polycomb complex in humans, but these areas don't attract the same proteins in mice. By swapping these human DNA segments into mice stem cells, it was shown that the local DNA sequence and DNA methylation status (another epigenetic mechanism) are very important in determining these differences.

Full list of publications:

1. Ziebart R, Antezana L, Crum O, Lynch MD, Wyles S. Laser and Energy Treatments for Acne Scarring: A Review. Journal of Drugs and Dermatology, In Press.
2. Sood A, Mansoor N, Memmi C, Lynch MD, Lynch JO. Generative Pretrained Transformer-4, an artificial intelligence text predictive model, has a high capability for passing novel written radiology exam questions. International Journal of Computer Assisted Radiology and Surgery. 2024. In Press.
3. Ganier C, Mazin P, Herrera-Oropeza G, Du-Harpur X, Blakeley M, Gabriel J, Predeus AV, Cakir B, Prete M, Harun N, Darrigrand JF, Haiser A, Wyles S, Shaw T, Teichmann SA, Haniffa M, Watt FM, Lynch MD. Multiscale spatial mapping of cell populations across anatomical sites in healthy human skin and basal cell carcinoma. Proc Natl Acad Sci, 2024. In Press.
4. Hughes S, Srenathan H, Lynch MD (Joint senior author), Leeman H. Multi-center experience from tertiary skin cancer units on the role of Sentinel Lymph Node Biopsy in patients with pT1b melanoma. Clin Exp Dermatol, 2023. In Press.
5. Shetty M, Ettlinger M, Lynch MD. GPT-4, an artificial intelligence large language model, exhibits high levels of accuracy on dermatology specialty certificate exam questions. medrxiv
6. Banila C, Green D, Katsanos D, Viana J, Osmaston A, Vasquez AM, Lynch MD, Kaveh S. A non-invasive method for whole-genome skin methylome profiling. British Journal of Dermatology. 2023. In press.
7. Mahil S, Choy SP, Kim BJ, Paolino A, Tan WR, Lim S, Seo J, Tan SP, Francis L, Tsakok T, Simpson M, Barker J, Lynch MD, Corbett M, and Smith C. Systematic review of deep learning image analyses for the diagnosis and monitoring of skin disease. npj Digital Medicine. In press.
8. Ganier C, Rognoni E, Goss G, Lynch MD, Watt FM. Fibroblast heterogeneity in healthy and wounded skin. Cold Spring Harbour Perspectives in Biology, In press.
9. Kravvas G, Asif M, Watchorn R, Castiglione F, Haider A, Freeman A, Hadway P, Hussain Alnajjar, Lynch MD, Bunker C. Male genital lichen sclerosus, micro incontinence and occlusion: mapping the disease across the prepuce. Clinical and Experimental Dermatology. In press.
10. Cunningham L, Ganier C, Ferguson F, White IR, Watt FM, McFadden J, Lynch MD. Gradient boosting approaches can outperform logistic regression for risk prediction in cutaneous allergy. Contact Dermatitis, 2021. In Press.
11. Ganier C, Harun N, Peplow I, Du-Harper X, Arthurs C, Watt FM, Lynch MD. ACE2 expression is detectable in keratinocytes, cutaneous appendages and blood vessels by multiplex RNA in situ hybridization. Adv Skin Wound Care, 2021. In Press.
12. Lakhan M, Lynch MD. Skin Pigmentation. Medicine 2021 (Review) DOI:https://doi.org/10.1016/j.mpmed.2021.04.010
13. Reynolds G, Vegh P, Fletcher J,… Lynch M,…Teichmann S, Watt F, Haniffa M. Developmental cell programs are co-opted in inflammatory skin disease. Science 2021 371(6527):eaba6500
14. Wan B1., Ganier C1., Du-Harpur X, Harun N, Watt F, Patalay R, Lynch MD. Applications and future directions for Optical Coherence Tomography in Dermatology (review). British Journal of Dermatology. In Press
15. Du-Harpur X, Arthurs C, Ganier C, Woolf RT, Laftah Z,Lakhan, MK, Salam A, Wan B, Watt FM, Luscombe NM, Lynch MD. Clinically-relevant vulnerabilities of deep machine learning systems for skin cancer diagnosis. Journal of Investigative Dermatology 2020 S0022.
16. Du-Harpur X, Luscombe N, Watt FM, Lynch MD. What is AI? Applications of artificial intelligence to dermatology. British Journal of Dermatology 2020 183:423.
17. Teo Y, McFadden J, White I, Lynch MD1. and Banerjee P1.. Allergic Contact Dermatitis in Atopic Individuals: Results of a 30-year Retrospective Study. Contact Dermatitis 2020. In Press 1.equal contribution
18. van de Lagemaat LN, Flenley M, Lynch MD, Garrick D, Tomlinson SR, Kranc KR, Vernimmen D. CpG binding protein (CFP1) occupies open chromatin regions of active genes, including enhancers and non-CpG islands. Epigenetics Chromatin. 2018 Oct 6;11(1):59.
19. Philippeos C, Telerman S, Oulès B, Pisco A, Shaw T, Elgueta R, Lombardi G, Driskell R, Soldin M, Lynch MD1. and Watt F, Spatial and single-cell transcriptional profiling identifies functionally distinct human dermal fibroblast subpopulations. 2018 138:811. 1.joint senior author
20. Lynch MD, Watt FM Fibroblast heterogeneity: Implications for human disease (review). Journal of Clinical Investigation 2018. 128:26-35.
21. Lynch MD, Lynch CNS, Craythorne E, Liakath-Ali K, Mallipeddi R, Barker JN and Watt FM. Spatial constraints govern competition of mutant clones in human epidermis. Nature Communications 2017. 8:1119.
22. Lynch MD, McFadden JP, White JM, Banerjee P, White IR. Age-specific profiling of cutaneous allergy at high temporal resolution suggests age-related alterations in regulatory immune function. Journal of Allergy and Clinical Immunology 2017. 140:1451-1453
23. Lynch MD, White JM, McFadden JP, Wang Y, White IR, Banerjee P. A dynamic landscape of allergen associations in delayed-type cutaneous hypersensitivity. British Journal of Dermatology 2017 176:184.
24. Jeziorska DM, Murray RJS, De Gobbi M, Gaentzsch R, Garrick D, Ayyub H, Chen T, Li E, Telenius J, Lynch MD, Graham B, Smith AJH, Lund JN, Hughes JR, Higgs DR, Tufarelli C. DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease. Proc Natl Acad Sci. 2017. 114:E7526-E7535.
25. Alwan W, Lynch M, McFadden J, White IR, Banerjee P. Patch testing in psoriasis patients: results of a 30-year retrospective cohort study. British Journal of Dermatology 2017 in press
26. Lynch MD, Ali F, Mallipeddi R. A pedunculated nasal nodule. British Medical Journal 2017 356:j763.
27. Lynch MD, Bashir S. Applications of Platelet-Rich-Plasma in Dermatology: A Critical Appraisal of the Literature. J Dermatol Treatment 2016. 27:285
28. Lynch MD, Sears A, Cookson H, Lew T, Laftah Z, Orrin L, Zuckerman M, Creamer D, Higgins E. Disseminated Coxsackievirus A6 affecting children with atopic dermatitis. Clin Exp Dermatol. 2014. 40:525
29. Lynch MD, Cliffe J, Morris-Jones R. Authors' reply to Cockayne and colleagues. BMJ 2014 348:g4092.
30. Lynch MD, Cliffe J, Morris-Jones R. Management of cutaneous viral warts. BMJ. 2014 348:g3339. Review.
31. Hughes JR, Roberts N, McGowan S, Hay D, Giannoulatou E, Lynch MD, De Gobbi M, Taylor S, Gibbons R, Higgs DR. Analysis of hundreds of cis-regulatory landscapes at high resolution in a single, high-throughput experiment. Nat Genet. 2014 46:205-12.
32. Lynch MD, Smith AJ, de Gobbi M, Flenley M, Hughes JR, Vernimmen D, Ayyub H, Sharpe JA, Sloane-Stanley JA, Sutherland L, Meek S, Burdon T, Gibbons RJ, Garrick D, Higgs DR. An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate Polycomb complex recruitment. EMBO Journal Nov 2011
33. Vernimmen D. Lynch MD, de Gobbi M, Garrick D, Sharpe JA, Sloane-Stanley JA, Smith AJ, Higgs DR. Polycomb Eviction as a New Distant Enhancer Function. Genes & Dev, 2011 25:1583-8.
34. Kowalczyk MS, Hughes JR, Lynch MD1., Garrick D1., Sharpe JA, Sloane-Stanley JA, McGowan SJ, De Gobbi M, Hosseini M, Vernimmen D, Brown JM, Gray NE, Collavin L, Gibbons RJ, Flint J, Taylor S, Buckle VJ, Milne TA, Wood WG, Higgs DR. Intragenic enhancers act as alternative promoters. Mol Cell 2012 45:447-458 1.equal contribution
35. De Gobbi M, Garrick D, Lynch MD, Vernimmen D, Hughes JR, Goardon N, Luc S, Lower KM, Sloane-Stanley JA, Pina C, Soneji S, Renella R, Enver T, Taylor S, Jacobsen SEW, Vyas P, Gibbons RJ, Higgs DR. Generation of Bivalent Chromatin Domains During Cell Fate Decisions. Epigenetics and Chromatin, 2011 4:9
36. Garrick D, De Gobbi M, Lynch MD, Higgs DR. Switching genes on and off in haemopoiesis. Biochem Soc Trans. 2008 36:613-8. (Review)
37. Lynch MD, Cariati M, Purushotham AD. Breast cancer, stem cells and prospects for therapy. Breast Cancer Res. 2006 8:211. (Review)
38. Lynch MD, Jones AE, Marker A, Grant JW, Purushotham AD. Malignant eccrine poroma in breast cancer-related lymphoedema. Ann R Coll Surg Engl. 2004 86:W32-5.
39. Lynch MD. How does cellular senescence prevent cancer? DNA Cell Biol. 2006 25:69-78. Review
40. Lynch MD. The role of cellular senescence may be to prevent proliferation of neighboring cells within stem cell niches. Ann N Y Acad Sci. 2004. 1019:191-4.