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  Newsletter Issue 6, 14 October 2013

Gold Sponsors

 

STEM CELL SOCIETY SYMPOSIUM 2013

"Early Human Development & Fetal-Maternal Medicine"

18 -19 November

Matrix Building Level 2 & 2M
30 Biopolis Street, Singapore 138671

Silver Sponsors

 

Bronze Sponsors

 

 

 

Dear Members, Delegates, Friends, and Colleagues

We are glad to present to you the Symposium 2013 Newsletter, Issue 6.

This newsletter features abstracts, bios and questionnaires of Rudolf Jaenisch from the Whitehead Institute & MIT, our keynote speaker for this year, and Lih Feng Cheow from the Institute of Molecular and Cell Biology, Singapore.

We also present two abstract selected speakers: Eugene Redmond, Yale University School of Medicine, and Gracy Rosario, Institute of Medical Biology, Singapore.

COUNT DOWN: times flying; only 34 days left to the opening of the symposium!!!

Updates:

Programme: A tentative programme has been made available here.

Symposium hotel: For our overseas attendees, we have negotiated a special room rate at the symposium hotel Park Avenue Rochester which is just across the road and in walking distance to the symposium venue. The hotel is also conveniently located close to public transport facilities such as the bus and the MRT networks. Considering staying in this hotel? Click here for more information.

Delegate Networking Event: A networking event open to all delegates of the symposium will take place on the first evening (18th November). Venue will be the Epicentre at Biopolis. Drinks and food should help stimulating interactions and communications among delegates.

DEADLINES:

IMPORTANT: Online Registration Closes: 4 November 2013!

To register, click HERE.

To learn more about the symposium, follow this LINK.

Contact us HERE.

Register today to enjoy excellent science and the networking opportunity with your colleagues and collaborators,

The Organizing Committee Stem Cell Society Singapore Symposium 2013

Featured Speakers  

KEYNOTE SPEAKER: Rudolf JAENISCH

Whitehead Institute & MIT, USA

 
Abstract  
iPS Cell Technology and Disease Research: Issues to be Resolved

 

The recent demonstration of in vitro reprogramming using transduction of 4 transcription factors by Yamanaka and colleagues represents a major advance in the field. However, major questions regarding the mechanism of in vitro reprogramming need to be understood and will be one focus of the talk. During cellular reprogramming only a small fraction of cells become induced pluripotent stem cells (iPSCs). Previous analyses of gene expression during reprogramming were based on populations of cells and impeded identification of events at the single-cell level. We utilized two different gene expression technologies to profile 48 genes in single cells at various stages during the reprogramming process. Analysis of early stages revealed considerable variation in gene expression between cells in contrast to late stages. Our data suggest

that stochastic gene expression early in reprogramming is followed by a late sequential phase with Sox2 activation upstream in a gene expression hierarchy. Subsets of downstream factors derived from the sequential phase can activate the pluripotency circuitry. A major impediment in realizing the potential of ES and iPS cells to study human diseases is the inefficiency of gene targeting. Using Zn finger or TALEN mediated genome editing we have established efficient protocols to target expressed and silent genes in human ES and iPS cells. The most recent advance comes from the use of the CRISPR/Cas9 system to engineer ES cells and mice. This technology allows the simultaneous editing of multiple genes and will facilitate establishing relevant models to study human disease. Using these gene editing approaches we are using patient specific iPS cells to study complex diseases such as RETT syndrome.

Biography PubMed

 

Dr. Rudolf Jaenisch is Professor of Biology at the Whitehead Institute and the Department of Biology, Massachusetts Institute of Technology. He has generated the first transgenic mice carrying exogenous DNA in the germ line and was the first to use insertional mutagenesis for identifying genes crucial for embryonic development. Perhaps his most fundamental contributions have been in the study of epigenetic processes during development.  In particularly he showed that methylation of DNA plays important roles in gene expression, imprinting and X-inactivation as well as in diseases such as cancer and mental retardation. 

His work has focused on mammalian cloning and has defined some of the molecular mechanisms that are crucial for the nuclear reprogramming. Most recently he is using direct reprogramming of somatic cells to generate “induced Pluripotent Stem” (iPS) cells in the culture dish. These cells are relevant to establish in vitro system to study major human diseases and eventually to derive cells that could be used for “customized” therapy.

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Lif Feng CHEOW

Institute of Molecular and Cell Biology, Singapore

 

 
Abstract  
Using microfluidics technology to perform single-cell DNA methylation analysis and multiplexed protein-protein binding assays  

In the early phase of development, epigenetic differences in a few progenitor cells eventually lead to the generation of lineage-specific cell types. Conventional bulk assays implicitly assume a homogeneous cell population; therefore a single-cell perspective of epigenetics is needed to reveal the intricate spatiotemporal regulation that gives rise to cellular diversity. However, single-cell analysis is technically challenging due to the large sample requirement in conventional DNA methylation assay (e.g. bisulfite sequencing). We developed a method based on methylation-sensitive restriction digest that enables DNA methylation analysis of single genomes with locus-specific resolution. Using microfluidics technology the assay can be multiplexed and many loci in a single cell can be addressed simultaneously. Applying this method to analyze single cells from 8-cell stage mouse embryos

deficient in TRIM28, we demonstrate for the first time epigenetic mosaic imprinting defects which may account for severe phenotypic variabilities observed in later stage embryos. In other work, we implemented a fluorescence anisotropy based binding assay in a combinatorial microfluidics chip to simultaneously interrogate >2,300 pairwise interactions. We demonstrated the utility of this platform in determining the binding affinity between chromatin-regulatory proteins and different post-translationally modified histone peptides. The microfluidics chip assay produces comparable results with conventional microtiter plate assays, yet requires two orders of magnitude less sample. This approach enables the use of small samples for medium-scale screening and could ease the bottleneck of large-scale protein purification.

Biography PubMed  

Lih Feng Cheow received his B.Sc. (Electrical and Computer Engineering) from Cornell University and his PhD (Electrical Engineering and Computer Science) from Massachusetts Institute of Technology, where he worked on developing microfluidics-based platforms for proteins and nucleic acids analysis.

In 2012 he joined the Microfluidics Systems Biology lab at the A*STAR Institute of Molecular and Cell Biology to work on using microfluidics tools for single-cell epigenetic analysis and high-throughput screening.

Interview  

What attracted you to a career in Science?

To start each day knowing that you’d learn something new by the end of the day

Who are your scientific heroes/role models and why?

Thomas Edison. For being the greatest inventor of all time.

What influenced you to pursue stem cell research?

Knowing that your research can potentially save lives.

What would you be if not a scientist/clinician?

An engineer.

What's the best advice you ever had?

I have not failed. I've just found 10,000 ways that won't work.

What’s your motto in life?

Do the best you can do in whatever you’re trying to do and never give up.

What will be the next major breakthrough in stem cell research?

Growing transplant organs for patients from their own cells.

 

Corrigendum

Ray DUNN

Institute of Medical Biology, Singapore

 

 

 

 

We apologize for incorrectly publishing Ray Dunn's affiliation in parts of our NewsLetters, Issue 5. The correct affiliation is shown above. To view the entire corrected NewsLetter, Issue 5, please click here.

 
Abstract Selected Speakers  

Eugene REDMOND

Yale University School of Medicine, USA

 
Abstract  
Improved method of differentiation of human stem cells produces better functional effects in a primate model of Parkinson’s disease  
Proof of principle for cell replacement as a treatment for Parkinson’s disease has been established in animal and some clinical studies.  Since Parkinson’s disease results when a significant portion of dopamine neurons are lost, replacement of these cells is a logical strategy, although there are many hurdles to be overcome.  It is not clear to what extent the Parkinson’s diseased brain is capable of supporting new cells and whether they migrate, overgrow, make appropriate synaptic connections, get rejected, or reverse all of the signs and symptoms of the disease. After promising results with human fetal dopamine precursors (Redmond et al. Science 242:768-771,1988) and neural stem cells derived from fetal brain (PNAS 104: 12175-80, 2007), our laboratories have used the same validated model of Parkinson’s, dopamine loss produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in Old World primates to study neural cells derived from embryonic stem cells and induced pluripotent stem cells following differentiation along the pathway to dopamine neurons.Cell types derived and differentiated from Wi-Cell lines H1 and H9 survived in substantial numbers in vivo over periods of many months. With or without augmentation by AAV5-transduced glial-derived neurotrophic factor, grafts of most of these cell types showed at most only small numbers of tyrosine hydroxylase positive cells.  We concluded that, in spite of significant numbers of cells characterized in culture as dopaminergic (expressing tyrosine hydroxylase and appropriately releasing dopamine) (Wakeman et al. Cell Transplant. Epub, 2013) such cells may not survive or be identical to the midbrain fetal dopamine precursor cells that survive long-term in vivo and maintain sustained dopaminergic function.   Therefore, we have now used the cell derivation protocol of Kriks et al. (Nature 480:547-51, 2011) to produce A9 midbrain dopamine cells and studied them in 3 monkeys over a period of 7 months, compared with untreated controls and other cell types. These cells distributed themselves broadly over the usual target areas in the striatum and substantia nigra, as seen in post mortem histology, and many were double labeled with selective markers for human grafts and for tyrosine hydroxylase.  Functionally, the treated monkeys showed greater reversal of parkinsonism, and over a broader range of severity, than any other stem cell type studied to date.  We believe that stem cells differentiated in this manner show promise for early clinical translation after more studies of safety and efficacy have been completed.
Biography PubMed  
D. Eugene Redmond, Jr., M.D., is Professor of Psychiatry and Neurosurgery and Director of the Neural Transplantation and Repair Program at the Yale University School of Medicine in Connecticut. He is also President and Founder of the Axion Research Foundation in the USA and the St. Kitts Biomedical Research Foundation in the West Indies, which carry out research in primates. His principal areas of research activity are stem cells and gene therapy as possible treatments for neurological disorders. His team was first to successfully transplant fetal brain tissue in monkeys and first to show gene expression from a viral vector in primate brain. Dr. Redmond went to Yale in 1974 from the Laboratory of Clinical Science at the National Institute of Mental Health and held Career Research Scientist Awards from 1980 to 2000, and multiple grants from NINDS, NIMH, and NIDA as principal investigator. He received the Foundation's Fund Prize from the American Psychiatric Association in 1981 and the Bernard Sanberg Award from the American Society for Neural Therapy and Repair in 2011. Dr. Redmond received his B.A. from Southern Methodist University in 1961, his M.D. from Baylor College of Medicine in 1968, and residency training in research psychiatry at the Illinois State Psychiatric Institute in Chicago. He is a member of the Society for Neuroscience, Fellow of the American College of Neuropsychopharmacology, the Movement Disorders Society, the American Gene and Cell Therapy Society, the International Society for Stem Cell Research, and former president of the American Society for Neural Therapy and Repair. Dr. Redmond has been a consultant and scientific advisor to pharmaceutical companies.
Interview  

What attracted you to a career in Science?

Since I was a child, I always wanted to know how things worked. As a result, I took a lot of things apart that I couldn’t get back together and got into trouble with my parents for ruining – like a clock. I had a piece left over and it wouldn’t tick. When I got to study the brain as a young researcher, the opportunity to repair and restore it was more compelling than studying lesions, electrical signals, images, and chemicals.

Which scientist/clinician has made the biggest impact in your field and why?

Harvey Cushing. Besides being a superb clinician, observer, and artist, he pioneered many techniques that are still used today. In many areas, he was ahead of his time – for example, his efforts to do “cell therapy” by transplanting brain tissue in 1909.

 

What influenced you to pursue stem cell research?

Stem cells were the next logical source of tissue for repairing the brain. Fetal tissue was difficult, controversial, and in short supply, so moving to neural stem cells in 1998 was a reasonable step. Similarly, embryonic and reprogrammed cells appear to have advantages..

What do you think of the opinion that stem cell research is ”hyped-up" with too many promises and too little deliveries?

Stem cell research did become over-hyped when political opposition tried to kill the field for ethical reasons. As a result, in their zeal to see it survive, scientists (amplified by the media) made it sound like cures were just around the corner. They will come, but the speed of scientific progress is always difficult to predict and the diminished funding because of the controversies has not helped to speed the benefits along.

Gracy ROSARIO

Institute of Medical Biology, Singapore

 
Abstract  
Dynamic Regulation of Canonical Wnt/b catenin Signaling by LIF in Preparation for Embryo Attachment  
In mammals, one of the important factors governing embryo implantation is leukemia inhibitory factor (LIF). In mice, LIF is expressed by the uterine endometrial glands on day 4 of pregnancy. It acts on the endometrial luminal epithelium (LE) to convert a non-receptive epithelium to an embryo receptive one. Deficiency of LIF in mice causes failure in both embryo attachment and subsequent stromal cell decidualization that can be rescued by a single intraperitoneal injection of LIF. However the downstream signaling and changes in gene expression induced by LIF in the luminal epithelium, the site of action of LIF, are still not deciphered. To identify the LIF driven signaling events, ovariectomized hormone stimulated mice were treated with a single dose of LIF. Luminal epithelium (LE) isolated from the uterus at 0, 1, 3 and 6 hrs was subjected to a microarray screen. One of the several key pathways regulated by LIF is canonical Wnt/catenin signaling. This pathway is dynamically altered by LIF in the uterus. Wnt7A, the only canonical Wnt/catenin ligand identified by this study and E-Cadherin, the adherens junction protein are altered in the LE within 1 hour of LIF exposure. LIF causes a reduction in E-Cadherin at the basal surface of the epithelium by 6hr.Activation of this pathway induces transient nuclear translocation of catenin at 3hr after which it reverts to the cell membrane by 6hr. Along with the activation of this canonical Wnt pathway in the LE, we observe a parallel activation in the underlying stromal cells. There we see nuclear localaization TCF1, TCF4 and LEF1, while the epithelial pathway only TCF4 changes. Cyclin D1, a Wnt target gene transiently increases in the LE and stroma at 1hr after LIF. Our results show that a transient LIF driven embryo independent Wnt/catenin signaling network exists in the murine uterus that may complement a previously described blastocyst dependent pathway. This pathway has not been previously identified. We predict that this pathway may a key LIF regulated essential to embryo implantation. Further analysis of this pathway will increase our understanding of the events involved in the enigmatic implantation phenomenon.
Biography PubMed  
My research interests involve analyzing gene regulation during embryo implantation and placentation in mammalian species. I received my doctoral degree in Biochemistry from the National Institute of Research in Reproductive Health, University of Mumbai (India) in 2006. My doctoral work identified the pre-changes to the classical epithelial plaque reaction in the endometrium, a prominent feature of pregnancy in non-human primates. The study provided strong evidence for estrogenic influences on primate endometrium during embryo implantation. I later pursued postdoctoral studies at the University of Kansas Medical Center, USA in the laboratory of Dr Michael Soares to study trophoblast stem cell fate during early events of rat placentation. This study identified the ability of low oxygen to shift development of trophoblast stem cells to the endovascular trophoblast lineage that alters the uterine vasculature for efficient fetal nutrient transport. In 2008, I joined the laboratory of Dr Colin Stewart at A*STAR lnstitute of Medical Biology, Singapore to pursue postdoctoral work on studying actions of the cytokine Leukemia Inhibitor Factor (LIF) on the mouse uterus. An intricate and complex network of events was observed to be initiated by LIF in the mouse luminal epithelium within a short timeframe of 6hrs. This information may help in rational development of non-steroidal contraceptives and improved treatments for female infertility as they provide molecular insights into the “refractory” and “receptive” phases of embryo implantation.
Interview  

What is your most memorable career achievement?

Detecting a single zoned hatched embryo in the uterus of non-human primates.

What attracted you to a career in Science?

A desire to understand how the environment drives varying adaptations in cells carrying the same genetic code.

Who are your scientific heroes/role models and why?

Drs James Watson and Rosalind Franklin for work on the DNA helix. Dr Allen C. Enders for his work on mammalian pregnancy.

Which scientist/clinician has made the biggest impact in your field and why?

Dr Robert Edwards for discovering IVF and bringing joy to lives of childless couples.

What would you be if not a scientist/clinician?

A historian.

What's the best advice you ever had?

Don’t ignore small accomplishments. They are the building blocks of your career.

What’s your motto in life?

There is always a reason behind every miracle.