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Expatriate Researcher Returns to Roost
With his wealth of knowledge and formidable experience, biotech scientist, Dr John Yu decided to move back to his homeland with aspirations to widen Taiwan’s biotechnology horizons and bring his country to prominence on the international stage of biotech research.

Dr Yu gave up his position as Director of Experimental Hematology, Department of Molecular and Experimental Medicine at The Scripps Research Institute to move back to his native Taiwan, determined to bring to his country international standards, experience and knowledge. He is currently the Distinguished Research Fellow at Institute of Cellular and Organismic Biology, and Genomics Research Center. In an exclusive interview, APBN’s Sonal finds out what makes this biotech scientist tick.

APBN: What is the current focus of your research? How is it important?

John Yu: I have assembled an interdisciplinary team of investigators in Academia Sinica, Taiwan, and formed a cohesive, interrelated team work to gather a better understanding of stem cell biology. Currently, our research aims to develop innovative technology platforms for identification of unique markers and regulators for normal and cancer stem cells. We employ glycomics/glycoproteomics, phosphoproteomics, coupled with scFv antibody library, and high throughput shRNA screening to interrogate differential profiles of glycans/glycoproteins in stem cells and differentiated cells and their downstream regulatory control. Now, launching the newly found markers of human embryonic stem cells (ESCs) or breast cancer stem/initiating cells (CSCs), we are trying to (a) investigate the role of these markers and their downstream regulators in the maintenance of the self-renewal capability and differentiation potentials of hESC, lung stem cells, and their CSCs, (b) isolate normal lung stem cells and identify CSCs for lung adenocarcinoma, (c) study the inter-relationship of biomarkers between normal stem cells and cancers, and (d) target CSCs, especially of breast cancer, and to explore the possibility of development of cancer therapeutics targeting CSCs with these biomarkers via specific antibodies or siRNA.

APBN: What are its potential applications?

John Yu: Specific surface markers are valuable for monitoring the culture and behavior of stem cells and their status of differentiation. Many commonly used stem cell markers were directly adopted from phenotypic characteristics of other cell types with limited insight into the specific stem cells under study. Therefore, it is important to identify new and more markers of stem cells. On one hand, this current project should help to sort out from the newly found surface markers those molecules that will facilitate the isolation and expansion of stem cells, and also help to shed light on the functional roles of these molecules in stem cells and CSCs. On the other hand, the innovative technology platforms developed in this project will not only promote the understanding of the relationship between stem cells and cancers, but also foster the development of cancer detection and therapeutics targeting new glycans /glycoproteins.

APBN: What are the milestones achieved by your lab?

John Yu: Based on MALDI-MS and MS/MS analyses, we have found a close association of the expressions of glycosphingolipids (GSLs) on the surface of hESCs with differentiation. It is believed that the newly found glycans present in hESCs could be candidates for cancer detection and glycan-targeted therapy of human tumors. SSEA-3 is a pentasaccharide (2Galß1? 3GalNAcß1? 3Gala1? 4Galß1? 4Glcß1) and serves as the precursor of Globo H. SSEA-4 is the sialylated derivative of SSEA-3 (NeuNAca2 -SSEA-3). On the other hand, Globo H, a known biomarker for cancers, was highly expressed uniquely in hESCs and its antibodies reacted with both Globo H and SSEA-3. Therefore, these markers for hESCs are perhaps the targets of therapy for cancers. We also showed that there was a striking switch in the core structures for globo- and lacto-series GSLs during differentiation of hESCs into embryoid body, neural progenitors, or endodermic cells, suggesting a close association of GSLs in hESCs with lineage-specific differentiation (PNAS 107 22564 2010; Stem Cells, 29: 1995 2011).

More recently, we employed glycoproteomics and glycan analysis to analyze the glycoprotein/glycan expression patterns for hESCs. It was found that seven newly found surface glycoproteins were also highly expressed in breast cancer stem/initiating cells. For example, ESC02 which is uniquely present in hESCs is highly expressed (at least 7 folds) in the paired cancer stem cell subpopulation of breast cancer from different patients versus non-CSC. When transduced with shESC02, the expression level of Sox2 in shESC02 cells was reduced to 40%, whereas no significant changes were seen in Oct4 and Nanog expression. In addition, gene knockdown of ESC02 expression leads to decrease in the self-renewal of both hESCs and mammary spheres of primary breast cancer from patients. Such ESC02 silencing in ESCs also results in developmental skewing toward endoderm/mesoderm differentiation in vitro and in vivo. Therefore, these results warrant the development of ESC02 as therapeutic agents for cancer, because knockdown of its expression fulfills the major requirements for new therapeutic agents of cancer: i.e. cell arrest and differentiation induction. Furthermore, shedding of ESC02 occurs to the medium after incubation with breast cancer cells. Thus, we had developed a platform to study the inter-relationship between stem cells and cancer and to develop new cancer detection method and glycan-targeted therapy.

APBN: Academia Sinica collaborates a lot with foreign universities. How is it helpful?

John Yu: Academia Sinica, the most preeminent academic institute in Taiwan was founded to pursue research excellence. There are 24 institutes and 7 research centers in Academia Sinica under three divisions: Mathematics and Physical Sciences, Life Sciences, as well Humanities and Social Sciences. At present, there are more than 1,500 researchers with Ph.D. degree and an annual budget over US$400 million. Among 246 academicians, there are six Nobel Laureates. The purpose of academic research is to improve human life. Academia Sinica will continue its tradition of pursuing solid research while exploring new knowledge and will remain focused on the needs of society in the hope of enriching human civilization.

Academia Sinica, with its own state of arts and expertise, also participates in the pursuit of research excellence worldwide. For example, President Chi-Huey Wong will visit the United States in late March 2012 along with 12 scholars from Academia Sinica. He will attend the “Future of Glycoscience” report committee meeting organized by the U.S. National Academy of Sciences; attend the Academia Sinica – UC Berkeley Symposium; give a lecture and sign a Collaborative Agreement at the University of California at San Diego; and receive Arthur C. Cope Award from the American Chemical Society. Such a visit is expected to boost academic cooperation between Taiwan and the United States.

In 2011, Academia Sinica President Emeritus Yuan-Tseh Lee officially took up the reigns of the International Council for Science (ICSU). He was inaugurated as President of this international organization during the General Assembly held in Rome, which was attended by over 300 ICSU representatives from around the world. Another example is the Yuan-Tseh Lee Array for Microwave Background Anisotropy (AMiBA) that is a forefront instrument for research in cosmology. This project is led, designed, constructed, and operated by extensive international and domestic scientific and technical collaborations. The facility is sited on Mauna Loa in Hawaii, USA, at an elevation of 3,400m to take advantage of higher atmospheric transparency and minimum radio frequency interference.

APBN: You were the Director of Experimental Hematology, Department of Molecular & Experimental Medicine, The Scripps Research Institute from 1998 to 2002 before you decided to move to Taiwan. What made you return to your country after working in US for more than three decades?

John Yu: In 2002, Professor Yuan-Tseh Lee, then President of Academia Sinica, offered me the position of the Director for Institute of Cellular & Organismic Biology (2002-2009) and the chief of Stem Cell Program. It was a great opportunity for me to do something for my country. In addition to pursue my own research, I set up a Stem Cell Program at the Academia Sinica, established the Taiwan Society for Stem Cell Research (www.tsscr.org.tw) and became its founding President.

I was also elected to serve in ISSCR International hESC Guidelines Task Force, Government Affairs Committee, and the Steering Committee of Stem Cell Network in Asia-Pacific regions. I had been in USA for more than 30 years; but the contributions which lead to personal satisfaction in your own motherland have been far greater than what one can expect to receive in the States.

APBN: Please elaborate on your role with the government of Taiwan with regard to Research and Development of Science in Taiwan

John Yu: In Taiwan, I serve on many advisory boards concerning biomedical research and biotechnology development.

I returned to Taiwan in 2002 and began efforts to establish a new Stem Cell Program in Academia Sinica. After successfully setting up a dynamic multidisciplinary program at the Genomics Research Center with approximately 80 personnel by May 2003, a newly renovated research lab was opened, providing the most up-to-date facilities for basic and translational research. The major emphasis of this Program is to pursue cutting edge stem cell research such as specific markers, pluripotency, and epigenetic control of normal and cancer stem cells. The members of this team participate in several national stem cell flagship programs from other institutes/universities.

One of my pioneer research achievements is the identification of a rare subpopulation of lung cells with the characteristics of pulmonary stem cells and the demonstration of their susceptibility to SARS-CoV and avian flu H5N1 (PNAS 103: 9530-9535, 2006). I am also trying to develop innovative technology platforms for identification of unique surface markers, and investigate the control of genetic regulators and epigenetic profiling affecting stem cells under the Flagship Program by combining several strategies including glycoproteomics and glycan analysis, phosphopeptide enrichment/LC/MS/MS analysis.

In 2005, Taiwan Society for Stem Cell Research was established and I became the founding President for this society (2005-2010). I was also the chief architect for the National Strategic Plan for Stem Cell Research in Taiwan since 2006. I was charged with the responsibility to set up National Strategy Plan for stem cell research. Under my leadership, a 4-point strategic plan was established: 1) establishing national flagship programs, 2) implementation of ethics and regulation, 3) setting-up infrastructures and resources, and 4) development of international collaborations. This strategy plan lays out the basic foundation and infrastructural support for stem cell research in Taiwan.

APBN: Taiwan is essentially a Buddhist country. Did the religious and social values affect Stem Cells research in anyway.

John Yu: The general public and patients in Taiwan hold enormous anticipation towards the development and success of stem-cell research. Since stem cell technology touches upon important ethical issues and public policy that required resolution, we had actively engaged with the public and hold extensive educational activities for the community. For example, we organized hearings for general public and proactively participated in the meetings organized by churches or Buddhist monks and nuns, to discuss ethical issues of stem cell research and potential values for the society. At the government level, we also formed a special Committee for Biotech, Ethics, & Social Communication 2010 to open up societal discourse and inform government policy related to new developments of biomedical technologies, such as stem cell research. Furthermore, since I was a part of ISSCR International hESC Guidelines Task Force, I actively advised the Department of Health in Taiwan to modify guidelines for stem cell research which now adheres to the international policy and regulations worldwide.

In order to ensure a role of Taiwanese stem cell researchers in international collaboration, Department of Health Executive Yuan in Taiwan had announced on August 9, 2007 a new regulatory guideline, “Policy Instructions on the Ethics of Human Embryo and Embryonic Stem Cell Research”. In addition, I actively worked to get National Legislation of Human Embryo and Embryonic Stem Cell Research Act approved, which was eventually passed in Executive Yuan on July 24, 2008. People in Taiwan have now realized that the development of ethical standards and practices is a critical catalyst for international collaboration and for research to be accepted ethically and for it to be validated by the scientific community.

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