Research Directions

Cancer Research
Cancer is the second cause of mortality worldwide and constitutes an increasing burden on human health. Cancer is a consequence of multiple genetic and epigenetic alterations that are either inherited or somatically acquired, and is easy to produce drug resistance and metastasis. Therefore, efficient and effective cancer treatment is still challenging and an urgent problem to solve. In hope to reduce cancer incidence and lethality that lead to improved human health, FHS conducts cancer research with particular focuses on 1) carcinogenesis and its signal transduction; 2) cancer genetics, epigenetics, and epidemiology; 3) cancer initiation, progression, metastasis; 4) metabolism and cancer; 5) cancer drug screening and development; and 6) cancer prevention and therapy.
In recent years, FHS has achieved remarkable results, including: 1) the use of global screening techniques such as CRISPR knockout technique, sleeping beauty transposon mutagenesis technique, next-generation sequencing technique to identify drivers that lead to the development and progression of cancers; 2) the establishment of a visible system to identify drivers for cancer cells in circulation, metastasis and during chemotherapy; 3) the employment of single cell sequencing and next-generation sequencing approaches (ChIP-Seq, RNA-Seq, and ChIA-PET) to define the molecular mechanisms of the transcriptional regulation by key mediators (including estrogen and androgen receptors) in cancer development; and 4) the exploration of the molecular mechanism of the cancer development through different models such as PRDMs, TETs, Sirtuins, CtBP, Angiotensin II knockout or knockdown models. These outputs lay a solid foundation for the next stage of the possible development of clinical applications.
It is our ultimate goal to develop new strategies for fighting against diseases that lead to better living standards of human. In clinical research aspect, our research team has: 1) developed the first open-access Chinese BRCA mutation database (dbBRCA-Chinese) for hereditary breast cancer; 2) identified a novel pyruvate dehydrogenase kinases (PDK) inhibitor from a large compound library to treat non-small cell lung cancer; 3) built a screening system to repurpose FDA-approved drugs in treating cancers with tumor suppressor mutations; and 4) developed several immunotherapeutic anti-cancer drugs such as anti-ADAM17 monoclonal antibody, venom-based peptides, bispecific antibodies and chimeric antigen receptor (CAR) T cell therapy. Hopefully, these new developments will enter next research phase with an ultimate goal of becoming a new line of medication that battles cancer.
Cancer Precision Medicine
Precision medicine is a medical model that tailors personalized therapeutic strategy according to the conditions of the individual patients. In order to meet the development of health care in Macao and the nearby region, FHS began this cancer precision medicine research initiative in Macao as early as 2015. As cancer deaths account for about one-third of all mortality in Macao, Dean DENG as the foremost pioneer in cancer research in the Greater China region decided to initiate this cancer precision medicine project in FHS, with particular emphases on colorectal cancer, lung cancer, breast cancer, liver cancer and nasopharyngeal cancer which are the most common cancers in Macao. The project requires the participation of medical institutions from which our research team collects samples from cancer patients for independent and detailed analyses. Based on the analyses, the research team proposes feasible treatment plans to doctors as references that assists the doctors in formulating precise and personalized treatment plan for each patient with an objective of providing the best treatment result with the least adverse effect that improves the life expectancy of the cancer patients.
The development of the medical research in Macao is highly innovative and groundbreaking. With the assistance of various internal and external parties, the research project on precision medicine is now on track and has achieved several important milestones and remarkable results in the recent years. They include: 1) the reception of ethics approval from the Macao Ethics Committee for Life Sciences to use human tissue samples for research, which signifies the debut of the project and more importantly, the initiation of cancer precision medicine research in Macao; 2) the initiative of the establishment of the cancer bank by collecting samples from local patients via local research collaboration; 3) the development of a platform to analyze patients’ samples and establishment of a drug library that contains over 20,000 drugs and chemicals for drug sensitivity test with the newly developed technologies, including the microfluidic chips for primary culture, the 2-dimensional (2D) culture at early passages, and the organoids at 3D culture; 4) the establishment of the analytical platform for the enormous data in bioinformatics; 5) the development of 24-hours anti-cancer drug screening biochip assay that integrates cutting-edge scientific expertise in precision medicine, microfluidic chip and image processing to screen cancer cells and tumor cells for drug sensitivity. FHS wishes to strengthen the collaborations with the hospitals in Macao to accelerate the pace to improve the living standard of the Macao community and the overall health standard in Macao.
Stem Cell and Development
The human body develops from stem cells through a programmed process. Stem cells possess the potential to become any cell type in the body and are present in many organs and tissues with the remarkable ability to repair and replace the damaged cells. Because of their unique properties, stem cells are increasingly becoming the central player in regenerative medicine and in treating many human degenerative diseases. FHS is making a concerted effort to understand how stem cells differentiate into various cell types and how they repair the damaged tissues and cells in the body, with an ultimate goal for developing innovative methods that make use of stem cells in the bedside applications.
Research and development in the field of stem cell and developmental biology in FHS has found immense success and established a promising niche for both basic and translational research in the last five years. A team of researchers are highly devoted in finding ways to treat several human diseases and advance the novel methods in biomedical research. FHS has accomplished several remarkable outputs in stem cell research and developmental biology. They include: 1) the potential therapeutic use of human embryonic stem cell-differentiated mesenchymal stem cells (MSCs) in treating autoimmune diseases such as multiple sclerosis and colitis; 2) the development of a novel method for stem cell transportation under ambient conditions without the need for the costly and inconvenient cryopreservation methods; 3) the discovery of the use of the anti-malarial Artemisinin in neuronal protection; 4) the invention of a cell culture medium, called E8 culture system, that is widely used in stem cell field world-wide; and 5) the identification of how the DNA modification enzyme controls the β-cell lineage specification during pancreas development. FHS is also working on the new differentiation methods to make heart and other organ cells as well as the development of the optimal culture condition for cell transplantation. It is in hope that these developments can soon be introduced in clinics as new therapeutics.
Aging, Neural and Metabolism Disorders
Macao is one of the regions in which the population has long life expectancy. Yet, its associated increase in the health care expense and reduction in productivity are predicted to bring heavy burden to the society. Almost all organs in human body degenerate to certain extent during aging, and many diseases including neurodegenerative diseases, cardiovascular disease, cancers, cataracts, osteoporosis, type 2 diabetes, and hypertension are results of the aging-related organ degeneration. Metabolic dysfunction is one hallmark that links aging-associated diseases, for instance the neurodegenerative Alzheimer’s, Parkinson’s and Huntington’s diseases. Furthermore, disturbed glucose metabolism, another example of dysfunctional metabolism, is common in the elderly and leads to type 2 diabetes with insulin resistance and high blood sugar level, obesity, high blood pressure, high serum triglycerides, low high-density lipoprotein (HDL) levels and high low-density lipoprotein (LDL) levels. These metabolic disorders not only are life threating but also cause other severe medical comprehensions. Many studies are focusing on these diseases, and no effective treatment are yet available.
FHS aims to develop animal models that mimic these aging-related diseases in roundworm and zebrafish. These disease models facilitate the investigation of the cause of these diseases, and shed lights onto the identification of the potential therapeutic targets and strategies for the treatment of these diseases. In the past several years, FHS has achieved remarkable results, including: 1) the establishment of animal models in roundworms for the neurodegenerative Alzheimer’s disease, hereditary sensory and autonomic neuropathy type 1, and in zebrafish for aging, all of which reveal the biology, pathophysiology and molecular mechanisms of these diseases; 2) the establishment of mouse models for metabolic disorders that identify inhibitors of some critical enzymes in glucose metabolism with strong anticancer efficacies; 3) the elucidation of how Artemisinin prevents and treats neuronal disorders including Alzheimer’s Diseases, Parkinson’s Disease and stroke; 4) the identification of the important genes in zebrafish that helps understand the aging process in vetebrates; and 5) the application of artificial intelligence to screen biomarker genes in blood for predicting the occurrence of Parkinson’s disease. These findings provide significant insights into the understanding of aging, neurodegenerative diseases and metabolic disorders and their associations in these diseases that lead to the development of potential therapeutic strategies. FHS has published many scientific papers in good scientific journals and successfully applied a few patents for these research findings.
Drug Development
There are ongoing needs to develop novel therapeutic interventions with a potential to be utilized in the clinics as unmet medical needs remain. FHS specifically emphasizes on finding the right molecules that can be used as drugs, and to identify the right drug targets with strong linkages to human diseases. This work provides an extra-dimension to complement the drug discovery efforts to pharmaceutical industry.
In the recent years, FHS has developed a range of powerful technologies to identify potential drug molecules. These include: 1) the identification of bioactive molecules from natural sources such as venom extracts or fungal metabolites to understand the mechanisms of drug action for enhancing the anticancer effects; 2) the development of monoclonal antibodies that are synthesized from cloned immune cells. These antibodies can be engineered with the in silico-derived yeast display technology to destroy tumor cells. FHS has further developed novel therapeutic anti-ADAM17 antibodies that target membrane enzyme ADAM17 have shown to be efficacious in a number of preclinical cancer models including ovarian cancer, breast cancer, pancreatic cancer and non-small cell lung cancer; 3) the chemical optimization of known bioactive molecules and high throughput screening of diverse compound library against drug targets to identify novel bioactive molecules. Novel dual target inhibitors targeting amyloid beta peptide aggregation and acetylcholinesterase have been developed to outperform the marketed acetylcholinesterase inhibitors in the Alzheimer’s disease mouse model; 4) the repurposing of marketed drugs for new indications; 5) the applications of synthetic lethality to identify pharmacological targets for non-druggable tumor suppressor mutations in cancer, and 6) the development of next generation of antibacterial reagents. These technologies have been applied successfully to discover a number of bioactive molecules showing remarkable efficacy against drug targets that strongly associated with cancers, neurodegenerative disease and infectious diseases.
Data Science
With the advances in technology, there is an increasing trend in applying large-scale, high-output approaches and techniques in biology and medical research, to generate large data. Hence, huge amount of data is constantly being generated and stored in databases. There is a strong need to process the information and extract knowledge quickly from this rapidly growing collection of data. Bioinformatics, a branch of data science, applies mathematics, computer science, and statistics to integrate, organize, understand and mine from such vast amount and currently-available biological information. These data sources are largely heterogeneous ranging from genome sequences, expression data from functional experiments, molecular structures, metabolic pathways, and protein-protein interaction networks. An effective and accurate extraction of useful information from these massive datasets ultimately facilitates the discovery of novel methodologies and tools to understand biological networks and processes.
In the recent years, FHS has put in enormous amount of resource to strengthen the research in data science. Data science research in FHS mainly emphases on systematically examining and understanding the extracted data for uncovering the biological significance. FHS has a few key projects, and they include the development of a database specific to the Chinese population for the tumor suppressors genes, BRCA and DNA mismatch repair genes. This is especially significant as the majority of the currently available data is derived largely from Caucasians of European and North American population, but the data are not necessarily applicable to the Chinese population. So far, FHS has identified 1,523 BRCA variants from 43,197 Chinese patients and 429 MMR variants from 33,000 Chinese individuals. This database provides important information for future research in cancers associated to the BRCA and MMR genes in Chinese population, and more importantly for a possibility for identifying individuals who carry risky mutations that may lead to breast cancer for early diagnoses.
To date, FHS has published more than 80 articles in highly reputable scientific journals that applied extensive amount of Bioinformatics in the research in highly reputable scientific journals.
Bioimaging
Biomedical imaging is a multidisciplinary subject that spans from basic biosciences to pre-clinical animal studies and clinical human investigations, and it has a wide range of applications, one of which is to apply in disease diagnoses. The use of imaging techniques to detect cancers at an early stage provides better opportunities for patients to obtain more effective treatments with fewer side effects. In addition, the development of novel non-invasive detection techniques, effective molecular probes, and nanoscale contrast agents for image-guided therapy/surgery customized at the individual patient level are in need urgently. These developments can provide daily monitoring of patient’s response, conduct monitoring of a tumor’s biomolecular response to treatment, quantify the efficacy of treatment and perform early prediction for drug response.
Since its establishment, FHS has invested a significant amount of resources in acquiring biomedical imaging instrument. Currently, FHS is equipped with state-of-the-art imaging platforms for in in vitro and in in vivo imaging, including commercial or home-made photoacoustic imaging/photoacoustic microscopy systems, 3D bioluminescence and fluorescence molecular imaging systems, multiphoton microscope, fluorescence/phosphorescence lifetime imaging microscope, light-sheet microscope, MRI, Micro-CT imaging system, 3D OCT imaging setup, several microscope imaging instrumentations and functional multimodal imaging systems. With these strong hardware supports, in the past several years, FHS has achieved national and international recognition through publishing in high-ranking journals in the biomedical imaging field, covering research advances in the fields of nanomedicine, cancer early diagnosis and therapy, macrophage biology, and medical spectroscopy. FHS is also working on other projects and making promising progress. A few current research projects include: 1) polyphenols based next generation nanomaterials for cancer theranostics; 2) the investigation of the dynamics of melanoma angiogenesis with multiphoton in in vivo microscopy; 3) the metabolic imaging of macrophages in a bleeding micro-environment; 4) the design of polymer nanothermometer for biomedical applications, and 5) the photoacoustic Imaging-guided precision brain glioma surgery using second-window near-infrared probes.
Structural Biology
Structural biology is the study of the three dimensional (3D) structures of proteins. Because proteins perform every chemical reaction in the cell, seeing the 3D structures of proteins allows scientists to understand how life fundamentally operates, which is important for drug development. A lot of diseases, including cancer, are caused by overactive proteins. With the 3D structures, scientists can design small molecules to inhibit and deactivate these overactive proteins, thus curing the diseases.
Nowadays, drug resistance evolves rapidly in pathogenic bacteria. Infection caused by these bacteria is a huge problem for immunosuppressed patients, for example cancer patients undergoing chemotherapy. These patients have weak immunity and conventional antibiotics are ineffective against infection by drug-resistant bacteria. Fortunately, most of these bacteria require some essential proteins to survive. By understanding the structures of these essential proteins, scientists can design new antibiotics to inhibit them, hence killing the bacteria and clearing the patients from infection.
FHS studies the functions and mechanism of important proteins in order to understand fundamental biology in diseases with structural biology and to develop new therapeutic agents. The remarkable scientific discovery on “Restoring the transcriptional activity by phosphorylation the oncogenic protein Bcl3 to inhibit its excessive activity” is published in Molecular Cell.