In brief

Delving for insights to reshape dermatology.

© A*STAR Research

Beyond skin deep

4 Jan 2024

From molecular methods to advanced optics, scientists are combining techniques and expertise from diverse disciplines to transform skin health research and fortify the body’s outermost barrier.

Whether to prepare for blazing sunshine or freezing winds, people have long turned to various methods to keep their skin in good shape. The skin’s value is more than just cosmetic; it’s a shield against radiation, toxins and microbes, and it’s a hub of sensors that help us feel the world.

A healthy, functional skin barrier is vital to our overall wellbeing. However, some conditions can put a wrinkle in our skin’s health, from irritating rashes to life-threatening wounds and cancers. As we age, our skin also naturally weakens as its component layers thin, lose their elasticity and regenerate more slowly.

Across the globe, scientists and physicians have long worked to navigate the complex frenzy of factors affecting our skin health, but humanity’s diversity means major gaps remain in our understanding thereof, said Steven Thng, Chief Dermatologist at the Skin Research Institute of Singapore (SRIS).

“Asian skin types are distinctly different from European counterparts, which means data from studies on the latter may be less relevant,” said Thng. “For example, with ageing, Asian skin tends to form more age spots, while Caucasian skin forms more wrinkles. We also see distinctly different mutations and immune profiles between them in conditions like atopic dermatitis (AD).”

Aiming to fill the gaps in Asian skin health research, A*STAR is directing its multidisciplinary expertise into initiatives like SRIS. A tripartite coalition between the A*STAR Skin Research Labs (A*SRL), the National Healthcare Group (NHG) and Nanyang Technological University (NTU) Singapore, SRIS unites scientists, clinicians and engineers in high-impact, interdisciplinary skin research that translates to improved patient care.

“Skin is a complex organ with intricate functions and studying it from multiple angles is fundamental to unravelling its multifaceted dynamics in health and disease,” said Sze-Wee Tan, Assistant Chief Executive of A*STAR’s Biomedical Research Council. “Our ability to marry deep biological and dermatological understanding of Asian skin with engineering know-how allows us to create innovative therapies, diagnostics and skincare products for patients and consumers alike.”

In partnership with other A*STAR institutes, industry and government, SRIS projects range from basic research on skin physiology to novel diagnostics and treatments. “We’re bringing people together to understand the clinical challenges of Asian skin, and to use our collective understanding to produce positive impacts for patients and consumers’ lives,” said Rachel Watson, Executive Director of A*SRL and SRIS.

Quenching immunity’s fires

Many common inflammatory skin conditions, such as AD and psoriasis, are linked to issues in our immune system. Aberrant cells and molecular pathways can overreact to perceived threats, releasing a flood of molecules that can inflame the skin, impairing the skin barrier and disrupting the normal life cycle of skin cells.

“While protecting us against multiple threats such as infection and cancer, the immune system drives many inflammatory skin conditions including AD and psoriasis,” said Florent Ginhoux, Senior Principal Investigator at SRIS and A*STAR’s Singapore Immunology Network (SIgN). “Studying its dysregulation is crucial to find new therapeutic approaches.”

AD is a key focus area at SRIS as it affects an estimated 20 percent of children and 11 percent of adults in Singapore. Also known as eczema, AD often manifests as dry, itchy skin patches and swellings which not only cause anxiety and discomfort but expose the skin to external irritants. While its exact cause remains unclear, AD has genetic components. “The Asian filaggrin mutation spectrum differs significantly from Western populations,” said Thng.

To tackle AD holistically for Asian patients, SRIS’s National Atopic Dermatitis Programme (NADP) brings together A*STAR researchers, National Skin Centre (NSC) clinicians and industry partners to clarify AD’s burden in Asian populations; develop new diagnostics and treatments; and aid patients in disease management. NADP includes large-scale studies that combine clinical, omics and imaging data to map AD’s pathogenesis and epidemiology.

“We’re examining the molecular mechanisms of skin barrier disruption, immunity and the exposome,” said John Common, A*SRL Deputy Executive Director, who jointly established NADP with Thng and Yik Weng Yew, NSC Deputy Head of Research.

To date, NADP has produced numerous publications, garnered five industrial research collaboration agreements and drawn over SGD$3.6 million in industry investments. Its work includes studies on cost-of-illness and quality of life for childhood AD; how inflammatory monocytes define immune dysregulation; and filaggrin gene sequencing to detect disease-associated variants.

“We are now aiming to develop our collective research findings into larger grant applications to further develop our ideas, advance our investigations of novel disease mechanisms, and apply our findings to the clinical cohorts developed within SRIS,” said Common.

Beyond NADP, SRIS also supports translational research by local biotech companies for novel AD therapeutics. These include phase 1b clinical trials for eblasakimab, a first-in-class monoclonal antibody developed by Aslan Pharmaceuticals and now in phase 2B multicentre trials.

Meeting the skin’s microbes

Skin health isn’t linked solely to cells in our skin, but also to their closest neighbours. From body odour to dandruff, many conditions are affected by the skin’s microbial community: diverse bacteria, fungi and viruses residing on the skin’s surface which also vary widely with genetics and environment. Molecules produced by this community can modulate skin’s inflammatory response, potentially triggering disease.

To examine these tiny worlds, researchers at SRIS and A*STAR’s Genome Institute of Singapore (GIS) launched the Asian Skin Microbiome Programme (ASMP). Co-led by Common, A*SRL Deputy Executive Director Thomas Dawson, and GIS Associate Director (Genome Architecture) Niranjan Nagarajan, ASMP initially focused on understanding healthy Asian skin, and how its microbiome was associated with health and disease.

“ASMP is driven by studies on humans using metagenomics, which provide snapshots of a whole landscape of microbial DNA,” said Nagarajan. “These not only reveal what organisms might be present, but the functional or metabolic pathways they affect in helpful or harmful ways. We’re also aiming to establish what a healthy baseline Asian skin microbiome looks like.”

Initially, ASMP set out to develop tools and optimise protocols, moving from marker gene-based taxonomic studies to whole-metagenome analyses. With time, it took on further technical challenges such as deconstructing the skin microbiome at increasingly higher resolutions, and reconstructing genomes of individual species from metagenomic data.

A large part of ASMP research focuses on fungal species such as Malassezia, their interactions with human hosts and microbial neighbours, and links to skin health and disease. Work led by Dawson recently found that Malassezia regulate our immune system and skin inflammatory status by producing lipid-based signalling molecules similar to human versions.

Now in its second phase of funding, ASMP is building a skin microbiome database from a large Singaporean cohort of over 2,000 individuals across 18 different skin sites. It is also collecting microbial isolates to build skin models for host-microbe interaction studies. “We’re aiming to develop our understanding of microbial functions to improve skin health and identify molecules for clinical trials,” said Common.

Working with clinicians from the National University of Singapore (NUS), National University Hospital (NUH) and NSC, ASMP also examine the skin microbiome’s links to specific diseases. These include not only skin diseases like AD—where studies show patients have perturbed microbiomes versus healthy counterparts, and an individual’s risk of severe disease can be stratified by the presence of certain microbial colonisation patterns—but also neurological conditions like Parkinson’s disease.

“In a recent study, we also found that the skin of children with recurring AD flares—despite decolonisation treatments—could be recolonised with disease-associated bacteria like Staphylococcus aureus through their caregivers, which means clinicians could factor them into AD treatment plans,” said Nagarajan.

Preserving skin integrity

The skin’s layers are constantly dividing to replace old cells with new copies. In the deeper dermal layer, a complex extracellular matrix provides the skin with strength, resilience and elasticity, and is a home for blood vessels and nerves. However, these can be impaired by age or other health conditions, like diabetes or hypertension.

"Anything that compromises our skin’s tissue integrity—its ability to build and maintain a strong, healthy barrier against the external environment—can lead to infections or wounds that impact quality of life,” said Leah Vardy, A*SRL Research Director and SRIS Senior Principal Investigator.

At A*STAR, chronic wounds and fragile skin in the elderly are two significant focus areas. In tropical climates, diabetic foot ulcers and bed sores are more infection-prone due to more robust microbial growth. Treatment can be challenging, with amputation a grim last resort.

SRIS’s Wound Care Innovation for the Tropics (WCIT) Programme aims to transform chronic wound care and reduce its economic burden through several research areas including preclinical wound models, innovative dressings and diagnostics, a first-of-its-kind chronic wound registry, and the world’s largest library of Asian chronic wound samples.

“With Singapore’s ageing population, chronic wounds pose an increasing burden on the national healthcare system, affecting around 12,000 patients a year,” said Yi Zhen Ng, WCIT Programme Manager. Ng highlighted a recent joint publication with the Ministry of Health, Duke-NUS and three tertiary hospitals which estimated chronic wounds cost the system US$350 million annually, and the population 2,077 quality-adjusted life years.

With A*STAR’s Institute for Infocomm Research (I2R) and the Diagnostics Development Hub (DxD Hub), A*SRL Senior Scientist Priya Bishnoi and colleagues are developing a digital platform that supports clinical decisions and home-based wound management. WCIT has also funded clinical projects with direct patient impact, such as the Lower Extremity Amputation Protection Programme (LEAPP), which reduced major and minor amputations in the NHG healthcare cluster by 35 and 80 percent over 18 months.

One major WCIT breakthrough is the development of the world’s first perturbed wound healing in vivo preclinical model to successfully capture many features of human chronic wounds. Developed by David Becker, a SRIS Senior Principal Investigator and Professor at LKC School of Medicine, and Jiah Shin Chin, an A*SRL Scientist, the model is being used to validate molecular pathways and therapeutics for wound healing and tissue repair. With this model, a unique hydrogel topical formulation was developed and validated, and will enter clinical studies at Changi General Hospital in early 2024.

Vardy, Thng and colleagues have also shown that polyamines, a family of metabolites, play a role in supporting skin barrier integrity and the wound healing response, with studies establishing links between aberrant polyamine levels and skin hyperpigmentation.

“Many complex factors—intrinsic and extrinsic—drive skin ageing,” said Vardy. “We want to understand the process and develop interventions to protect and treat age-associated skin phenotypes.”

Diagnosing at depth

The sheer diversity of skin conditions can make accurate diagnoses challenging. “Individual perceptions of skin conditions may vary; it’s difficult to establish a universally applicable standard for what constitutes healthy skin,” said A*SRL’s Malini Olivo, Distinguished Principal Scientist at the Translational Biophotonics Laboratory (TBL).

However, advanced technologies such as non-invasive imaging and artificial intelligence are enabling a clearer view of skin health. A*STAR’s work in biophotonics and bioengineering has pioneered the development of cutting-edge devices that play a crucial role in clinically assessing skin disorders.

“Through our strategic alliance with NSC and NUH, we are gaining new insights on individual differences in skin composition, health, stress responses and therapeutic efficacy,” said Olivo. “This collaborative effort extends beyond research, as A*STAR has actively generated multiple IPs through its technological innovations, which in turn have attracted industry partners from consumer healthcare looking to validate their products.”

In groundbreaking first-in-human studies, TBL and NSC are successfully employing handheld versions of two optoacoustic technologies for dermatological applications: photoacoustic imaging (PAI) and confocal Raman spectroscopy (CRS). These innovations enabled non-invasive, label-free analyses of various skin conditions including cancer, psoriasis and AD.

"The handheld PAI facilitated precise 3D tumour imaging to create dimension maps with exceptional correlation with histological data, which could simplify surgical procedures and streamline prospective cancer studies,” said Olivo. “Meanwhile, CRS played a pivotal role in evaluating skin biochemical changes —water, ceramide, urocanic acid—in AD and psoriasis patients, enabling objective assessment and treatment monitoring.”

Working with NSC clinicians, A*STAR’s Bioinformatics Institute (BII) also developed machine learning (ML) models to analyse raster-scanning optoacoustic mesoscopy (RSOM) data. RSOM 3D images are derived from sound pressure waves that travel through skin tissue, collecting features about lesion sites and swollen areas. Connecting ML tools that rapidly extract patterns from these images can then help clinicians detect AD with greater accuracy and efficiency.

A*SRL not only engages with other research institutions and hospitals, but also pushes technology breakthroughs to the market through strategic partnerships with SMEs. “These collaborative endeavours position A*STAR as a key player in advancing the diagnosis and treatment of skin disorders, while fostering innovation and commercialisation in the field,” said Olivo.

Redefining skincare

Over the last two decades, strong collaborations between academics, clinicians and industry have driven a revolution in skin biology. “We’ve moved from draping psoriasis patients in coal tar-soaked bandages, to giving them oral drugs or injections that subdue or even resolve disease,” said Rachel Watson.

Persistent clinical gaps now guide cross-disciplinary efforts to decipher the individual differences in skin health and the aberrant molecular pathways responsible for diseases. Excitingly, researchers are gaining the technological tools to dig deeper into various layers of skin biology, from its biochemical balance and resident microbiome to inflammatory regulators and self-repair processes.

Continued support for skin research, shared knowledge databases and more effective medical devices are elevating the standard of care for both disorders and subclinical conditions, empowering people of all ages and backgrounds to feel confident in their own skin.

“There is a paradigm shift in the value placed on Asian skin health, as well as skin research in Singapore and worldwide. We can easily envision a future where advanced technologies merge with a profound understanding of individual skin biology across age groups, offering tailored solutions that prioritise not just aesthetics but holistic skin health for all,” said Sze-Wee Tan.

“Our long-term goal is to put ourselves out of a job: to solve everyday problems faced by our clinical colleagues, to fortify the skin of the elderly, to cure skin disease,” said Watson.

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This article was made for A*STAR Research by Wildtype Media Group