Chemical-only Cell Reprogramming Transforms Human and Mouse Skin Cells into Neurons

Chemical-only Cell Reprogramming Transforms Human and Mouse Skin Cells into Neurons

Friday, 07 August 2015

Two labs in China have independently succeeded in transforming skin cells into neurons using only a cocktail of chemicals, with one group using human cells from healthy individuals and Alzheimer's patients, and the other group using cells from mice. The two studies reinforce the idea that a purely chemical approach is a promising way to scale up cell reprogramming research that may avoid the technical challenges and safety concerns associated with the more popular method of using transcription factors. Both papers appear on August 6 in the journal Cell Stem Cell.

One of the challenges of forcing cells to change identity is that the cells you end up with may look normal but have different internal activities than their naturally forming counterparts. The two papers provide evidence that similar gene expression, action potentials, and synapse formation can be detected in transcription-factor-induced neurons as those generated from the chemical cocktails. (Both groups used mixtures of seven small molecules, but different recipes – outlined in detail in the supplemental information section of each paper – because they focused on different species.)

This is an image of mouse chemical-induced

neurons. Credit: Courtesy of Hongkui Deng.

"We found that the conversion process induced by our chemical strategy is accompanied by the down-regulation of [skin-cell] specific genes and the increased expression of neuronal transcription factors," said human study co-author Jian Zhao, of the Shanghai Institutes for Biological Sciences and Tongji University.

"By coordinating multiple signalling pathways, these small molecules modulate neuronal transcription factor gene expression and thereby promote the neuronal cell transition."

The authors add that the direct conversion bypasses a proliferative intermediate progenitor stage, which circumvents safety issues posed by other reprogramming methods.

This is an image of human chemical induced

neurons. Credit: Courtesy of Gang Pei and

Jian Zhao.

Zhao's paper, co-led with cell biologist Gang Pei, also shows that the pure chemical protocol can be used to make neurons from the skins cells of Alzheimer's patients. Most of the work using patient stem cells has been done by using transcription factors – molecules that affect which genes are expressed in a cell – to create induced pluripotent stem cells. Chemical cell reprogramming is seen as an alternative for disease modelling or even potential cell replacement therapy of neurological disorders, but the "proof-of-concept" is still emerging.

"In comparison with using transgenic reprogramming factors, the small molecules that are used in this chemical approach are cell permeable; cost-effective; and easy to synthesize, preserve, and standardize; and their effects can be reversible," says mouse study co-author Hongkui Deng of the Peking University Stem Cell Research Center.

"In addition, the use of small molecules can be fine-tuned by adjusting their concentrations and duration, and the approach bypasses the technical challenges and safety concerns of genetic manipulations, which may be promising in their future applications."

Deng worked for four years with Zhen Chai and Yang Zhao, also of Peking University, to identify the small molecules that could create chemically induced mouse neurons. Researchers had been close for years, but a transcription factor was always necessary to complete the transformation. Through many chemical screens they identified the key ingredient, I-BET151, which works to suppress transcription in skin cells. They then found the right steps and conditions to mature the neurons post-transformation.

The authors of both papers aim to learn more about the biology behind chemically induced reprogramming and to make the protocols more efficient. While their success is promising, there are still a number of hurdles to overcome.

"We hope in the future that the chemical approaches would be more robust in inducing functional mature neurons," Deng says.

"In addition, we are attempting to generate specific neuronal subtypes and patient-specific functional neurons for translational medicine by using pure chemicals."

Jian Zhao, of the human study, says:

"It should be possible to generate different subtypes of neurons with a similar chemical approach but using slightly modified chemical cocktails."

"It also needs to be explored whether functional neurons could be induced by chemical cocktails in living organisms with neurological diseases or injury," she adds.

Source: Cell Press

Contact: Joseph Caputo

References:

Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons

Xiang Li, Xiaohan Zuo, Junzhan Jing, Yantao Ma, Jiaming Wang, Defang Liu, Jialiang Zhu, Xiaomin Du, Liang Xiong, Yuanyuan Du, Jun Xu, Xiong Xiao, Jinlin Wang, Zhen Chai, Yang Zhao, Hongkui Deng

Cell Stem Cell Volume 17, Issue 2, p195–203, 6 August 2015

Direct Conversion of Normal and Alzheimer's Disease Human Fibroblasts into Neuronal Cells by Small Molecules

Wenxiang Hu, Binlong Qiu, Wuqiang Guan, Qinying Wang, Min Wang, Wei Li, Longfei Gao, Lu Shen, Yin Huang, Gangcai Xie, Hanzhi Zhao, Ying Jin, Beisha Tang, Yongchun Yu, Jian Zhao, Gang Pei

Cell Stem Cell Volume 17, Issue 2, p204–212, 6 August 2015

.........

ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at

http://cellnews-blog.blogspot.com/

---

BGI Researchers Uncover Extensive RNA Editing in a Human Transcriptome

BGI Researchers Uncover Extensive RNA Editing in a Human Transcriptome

Wednesday, 15 February 2012

In a new study published online in Nature Biotechnology, researchers from BGI, the world's largest genomics organization, reported the evidence of extensive RNA editing in a human cell line by analysis of RNA-seq data, demonstrating the need for new robust methods to identify important post-transcriptional editing events.

RNA editing is a normal but not yet fully understood process in which small nucleotide changes occur after DNA has been transcribed into RNA. It is an integral step in generating diversity and plasticity of cellular RNA signature as a post-transcriptional event that recodes hereditary information. RNA editing is an important area in the post-genomic era for its role in determining protein structure and function. It has become increasingly important in genetic research.

Last year, a study published in Science (Li, et al. Science, May 19, 2011) reported a large number of sequence differences between mRNA and DNA in the human transcriptome. This finding was startling because it implied that there might be a still undiscovered mechanism of 'RNA editing' that could disrupt the central dogma and affect our understanding of genetic variation. However, this view was strongly contested by other scientists because of the technical issue and lack of academic rigor, such as sequencing error or mis-mapping. In this latest study, BGI researchers developed a more rigorous pipeline for approaching these problems and answered some of the concerned questions, which contributed to paving way for the further studies of this field.

They obtained the whole-transcriptome data by RNA-seq from a lymphoblastoid cell line of a male Han Chinese individual (YH), whose genome sequence was previously reported as the first diploid genome of Han Chinese. RNA-seq, also known as "Whole Transcriptome Shotgun Sequencing", is a recently developed approach on transcriptome profiling that uses deep-sequencing technologies with the advantages of high-throughput data, low background, high sensitivity and repeatability. In a paper published in 2009 in Nature ReviewsGenetics, RNA-seq is referred to as a revolutionary tool in transcriptomics.

"We used RNA-seq in the study to identify post-transcriptional editing events, and developed a computational and comprehensive pipeline to find the human RNA editing sites," said Zhiyu Peng, the leading author of the paper and Vice Director of Research & Cooperation Division of BGI. The pipeline was used to identify the extensive RNA editing from genome and whole transcriptome data by screening RNA-DNA differences of the same individual through successive quality control filters.

Through this pipeline, BGI researchers identified 22,688 RNA editing events, and found most editing events (~93%) convert adenosine (A) into inosine (I), which in turn is read as guanosine (G), in consistence with known editing mechanisms based on adenosine deaminase acting on RNA (ADAR). They also found 44 editing events in microRNAs (miRNA), suggesting there is a potential connection between RNA editing and miRNA-mediated regulation. Researchers also found in the study evidence of other types of nucleotide changes, but these were validated at lower rates.

"These findings demonstrate this multifilter molecular pipeline is an excellent approach in this study," said Peng.

"With the multiple filters, false positive results can be controlled or eliminated while identifying RNA editing events, providing a more accurate and effective method to extensively analyze RNA editing. We now plan to apply this new methodology to larger-scale deep sequencing studies for more comprehensive analysis and profiling of editome, including studies with additional physiologically relevant samples."

"The evidence of extensive RNA editing identified in a human transcriptome underscores the necessity of an effective method to fully detect these events in order to further advance our understanding of human development and normal pathophysiological condition," said Jun Wang, Executive Director of BGI.

"With continual improvement of the new approach, we believe this could be achieved in the near future."

About BGI

BGI was founded in Beijing, China on September 9th, 1999 with the mission of being a premier scientific partner to the global research community. The goal of BGI is to make leading-edge genomic science highly accessible through its investment in infrastructure that leverages the best available technology, economies of scale, and expert bioinformatics resources. BGI, and its affiliates, BGI Americas, based in Cambridge, MA and BGI Europe, based in Copenhagen. Denmark, have established partnerships and collaborations with leading academic and government research institutions as well as global biotechnology and pharmaceutical companies, supporting a variety of disease, agricultural, environmental, and related applications.

BGI has established a proven track record of excellence, delivering results with high efficiency and accuracy for innovative, high-profile research which has generated over 170 publications in top-tier journals such as Nature and Science. These accomplishments include sequencing one percent of the human genome for the International Human Genome Project, contributing 10 percent to the International Human HapMap Project, carrying out research to combat SARS and German deadly E. coli, playing a key role in the Sino-British Chicken Genome Project, and completing the sequence of the rice genome, the silkworm genome, the first Asian diploid genome, the potato genome, and, most recently, 1000 genomes and human Gut meta-genome.

Source: BGI Shenzhen

Contact: Jia Liu
.........

ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at

http://cellnews-blog.blogspot.com/

---

Cell Transplants May Benefit Children with Cerebral Palsy

Cell Transplants May Benefit Children with Cerebral Palsy
Monday, 19 April 2010

A unique cell type that supports and surrounds (ensheathes) neurons within the nose (olfactory system) known as olfactory ensheathing cells (OECs), possess the ability to regenerate, are relatively easy to obtain, and have become prime candidates for transplantation to repair a number of lesions in the central nervous system (CNS). Transplanted OECs, known to retain exceptional plasticity and promote olfactory blood vessel growth while offering neuroprotection, have been demonstrated to be potentially useful for a number of neurological disorders, including multiple sclerosis, spinal cord injury and amyotrophic lateral sclerosis (ALS).

A group of Chinese researchers hypothesized that OECs might also hold promise for treating cerebral palsy (CP), a neurological disorder appearing in infancy or early childhood and characterized by its permanent effects on muscle movement. The study is published in issue 19(2) of Cell Transplantation.

"CP is a class of brain lesion in children with a wide variety of causes - from abnormal brain development to peri-natal injuries - and manifesting in progressive physical dysfunction," said corresponding author Dr. Hongyun Huang of the Beijing Rehabilitation Center.

"We conducted a randomized, controlled clinical trial with 33 volunteers, 14 of whom completed the six-month study, to determine if transplanted OECs were effective in treating children and adolescents with CP, given that CP shares many of the same features of other degenerative diseases."

According to the researchers, 83 percent of the children with CP that they examined had abnormal radiological findings, with white matter damage being the most common abnormality. Tissue loss, inadequate or delayed myelination, glial scars and shrunken white matter of the brain were also encountered. The white matter is made up of nerve fibres communicating between brain areas.

The research team's hypothesis and protocol was developed with prior knowledge of a key location in the brain's frontal lobes (defined as the "Key Point for Neural network Restoration (KPNNR)" based on previous studies) for injecting OECs and that the injected OECs would produce Schwann cell-like myelin sheaths around demyelinated axons.

Results were measured by both the Gross Motor Function Measure (GMFM-66) and the Caregiver Questionnaire Scale.

"This trial, albeit small in sample size, indicates that OEC KPNNR transplantation may be effective for functional improvement in children and adolescents with CP," said Dr. Huang.

"Our results showed that transplanting OECs into CP patients could improve the neurological function of the patients and did not cause significant side effects. The procedure may be a plausible method to treat this as yet incurable disorder."

"In parallel with recently FDA-approved US clinical trials of cell therapy for adult stroke and cerebral palsy, this clinical study in China advances the use of stem cells for treating brain disorders, but a very careful assessment of this experimental treatment needs to be exercised in order to gauge its safety and efficacy," says Cell Transplantation associate editor Dr. Cesar V. Borlongan.

Reference:
Intracranial Transplant of Olfactory Ensheathing Cells in Children and Adolescents With Cerebral Palsy: A Randomized Controlled Clinical Trial
Chen, Lin; Huang, Hongyun; Xi, Haitao; Xie, Zihang; Liu, Ruiwen; Jiang, Zhao; Zhang, Feng; Liu, Yancheng; Chen, Di; Wang, Qingmiao; Wang, Hongmei; Ren, Yushui; Zhou, Changman
Cell Transplantation, Volume 19, Issue 2, pages 185-191, DOI: 10.3727/096368910X492652
.........


ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at
http://cellnews-blog.blogspot.com/

---

Stem Cell Research in China

From molecular physiology to therapeutic applications Wednesday, 29 July 2009 Stem cell research promises remedies to many devastating diseases that are currently incurable, ranging from diabetes and Parkinson's disease to paralysis. Totipotent embryonic stem cells have great potential for generating a wide range of different human cells that can be used to restore malfunctioning or damaged cells and tissues in patients. Recent studies have shown that pluripotent stem cells derived from adult bone marrow, the umbilical cord and the placenta could also be induced to differentiate into a variety of different tissues. In this issue, we have invited several scientists in China to summarize their pioneering works in the stem cell research field in the current issue of Science in China Series C - Life Sciences. Since 2001, Dr. Alex Yu Zhang has been a professor at Capital Medical University in Beijing and is Director of Cell Therapy Center at Xuanwu Hospital. His current research interest focuses on the understanding of basic biological properties of stem cells and developing nonhuman primate models for stem cell-based therapy of degenerative diseases. He has developed a stem cell mediated expression system for treating Parkinson's disease and his research using pancreatic progenitor cells for treating diabetes has demonstrated efficacy in monkey models. Professor Zhang has written an overview of cell replacement therapy of Parkinson's disease, which has been studied in both animal models and human patients for more than 20 years. Recent progress in stem cell biology has indicated that it is possible to avoid immunorejection of either nuclear transfer embryonic stem cells or induced pluripotent stem cells. On the other hand, recent post mortem analysis of patients who received foetal brain cell transplantation revealed that implanted cells are prone to degeneration just like endogenous neurons. Thus it appears that future cell replacement studies will have to focus on ameliorating disease symptoms as well as on slowing the progression of the disease [1]. Professor Robert Chunhua Zhao from the Chinese Academy of Medical Sciences is Executive Director of the National Center for Stem Cell Research. His group has taken stem cell therapy into phase II clinical trials in China, and is the leading runner in stem cell therapeutics. They have identified a mesenchymal stem cell (MSC) population from human foetal bone marrow and found that these cells could differentiate not only into osteogenic, adipogenic and endothelial lineages, but also hepatocyte-like cells, and neural and erythroid cells. They remained in some tissues and organs during gestation, could give rise to different kinds of pluripotent stem cells, and thus could potentially contribute to self-repair and self-renewal of tissues and organs. They generated cells not only for the damaged tissues in which they reside, but also for damaged tissues at other locations in the body via migration triggered by pro-inflammatory cytokines and growth factors. The potential use of MSCs in tissue regeneration has been shown in several models, including skin, muscle, lung, heart and the small intestine. MSCs have emerged as a promising therapeutic modality for tissue regeneration and autoimmune disease, although the mechanisms underlying the immune-modulatory effects of MSCs have not yet been clearly defined. In this review, Professor Robert Zhao summarizes the current literature on the complex mechanism of MSCs' immune modulation and clinical studies, and discusses future directions for utilizing MSCs for clinical treatments [2]. Professor Hongkui Deng from Peking University is working on the differentiation of human embryonic stem cells into pancreatic beta cells to treat diabetes. He is one of the two winners in China of the Bill and Melinda Gates Foundation's "Grand Challenges in Global Health". He obtained $1.9 million for his proposal to use stem cells to create mouse models for testing HIV and hepatitis C vaccines. Professor Deng has written a summary of recent progress in human embryonic and inducible pluripotent stem cell differentiation into functional pancreatic islet cells and discusses the challenges for future work [3]. Professor Qi Zhou is assistant Director of the Institute of Zoology at the Chinese Academy of Sciences. He has been studying the mechanism of differentiation and de-differentiation, cellular plasticity and totipotency of pluripotent cells, as well as that of somatic cells. He intends to build various cellular and animal models for human diseases, to uncover mechanisms underlying these different cellular processes and to discover new ways to improve cloning efficiency, which will provide a powerful tool for the study of mammalian reprogramming and ultimately offer important opportunities for regenerative medicine. Professor Zhou has helped to build the National Stem Cell Bank in Beijing, where clinical grade stem cell lines and patient specific cell lines have been created for future drug target candidate screening and therapeutic applications. Professor Qi Zhou has written a summary on human parthenogenetic embryonic stem cells as one potential resource for stem cell therapy[4]. Professor Lin Liu from Nankai University has been working on creating versatile patient-specific pluripotent stem cell lines that can be reliably used to fulfil the promise of stem cell therapy in regenerative medicine. Dr. Lin Liu's group found that pES cells generated from immature oocytes in mice exhibit pluripotency resembling fES cells, as evidenced by similarly high chimera production and germline transmission. Thus, immature eggs may provide an efficient source of autologous stem cells for regenerative medicine. This group also tested whether pESCs can be generated from older females. Dr. Lingyi Chen works on mechanisms of early embryonic differentiation. In their review of current special topics on stem cells, Drs. Lingyi Chen and Lin Liu analyze the current state of iPS research, particularly on limitations and advancements in this field, and propose possible future directions to meet the challenges of iPS cells for clinical applications [5]. Stem cell research has made significant progress in the past decade. Some therapeutic applications are coming closer to being on the market, but it is still hard to predict if and when stem cell therapy will replace largely traditional therapeutics. Given the early indications for success, we hope to see promising remedies for the many current incurable diseases being made available in the clinic over the coming years. References: 1 Ren Z, Zhang Y. Cell therapy for Parkinson's disease - So close and so far away. Sci China C-Life Sci, 2009, 52: 610—614 2 Wang L, Zhao R C. Mesenchymal stem cells targeting the GVHD. Sci China C-Life Sci, 2009, 52: 603—609 3 Zhang D, Jiang W, Shi Y, et al. Generation of Pancreatic islet cell from human embryonic stem cell. Sci China C-Life Sci, 2009, 52: 615—621 4 Hao J, Zhu W, Sheng C, et al. Human parthenogenetic embryonic stem cells: One potential resource for cell therapy. Sci China C-Life Sci, 2009, 52: 622—636 5 Chen L, Liu L. Current progress and prospect of induced pluripotent stem cell. Sci China C-Life Sci, 2009, 52: 622—636 ......... ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html

---

China Restrict Clinical Tests of Stem Cells Obtained by Therapeutic Cloning

Other medical procedures also restricted Tuesday, 17 March 2009 China's Ministry of Health has issued a temporary ban on clinical use of therapeutic cloning, effective from May 1, on its official Web site on Tuesday. The MoH also prohibited other techniques, like xenotransplantation of stem cells and some gene therapy trials in clinical studies. Article 58th in the guidelines stated: “…xenogeneic stem cell therapy technology, xenotransplantation gene therapy technology, human somatic cell cloning technology in medical technology may not be used in clinical suspense.” This temporary ban is issued because of major concerns on ethical issues, safety, and effectiveness, until further verification of the technologies are achieved. The restrictions are applied to a broader set of clinical techniques. They also include treatment by cloning technologies, autologous stem cell and immune cell therapy, gene therapy techniques, xenotransplantation technology, surgical treatment of central nervous system, stereotactic surgical treatment of mental illness technologies, allogeneic stem cell transplantation technology, and vaccines as therapeutic techniques. It is uncertain how these restrictions will affect new medical procedures in the long run. However, it shows a sensitivity to the complexity of these issues in the medical community in China. These new restrictions should also be seen in the light of the recently initiated medical reform program in China. "The biggest beneficiaries of medical reform are the masses of the people, the goal is to benefit everyone." China’s health minister Chen Zhu said in a recent interview with Xinhua. ......... ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html

---

Human Genomics in China

10-year endeavor: from planning to implementation Wednesday, 07 January 2009 By Chen Zhu and Zhao Guo-Ping Ten years ago, the Chinese National Human Genome Center at Shanghai (South Center, hereafter) was established in the Zhangjiang HiTech Park of Pudong District in Shanghai. To commemorate this important event, which marks the beginning of the Genomics Era in China, we specially organize a series of mini-reviews for this special issue. We hope that this effort may draw the attention of the Chinese life science research workers to collectively recall the short but fruitful history of human genome project and co-ordinately explore the trend and goal of the future development of this academic discipline in China. As early as in the late 1980s, the Chinese High Technology Research and Development Program, which is also known as the 863 Program, funded the scientists of Fudan University (in Shanghai) to construct DNA jumping library for human genetic disease related physical mapping. It was probably the very first human genome related research project supported by a national funding agency. After 1991, Fudan University, Ruijin Hospital and the Cancer Research Institute in Shanghai were all funded by the 863 Program in succession, to develop genomics technology by means of molecular genetics, and to study genetic diseases including cancer by means of medical genetics. Meanwhile, Beijing scientists such as those in the Institute of Basic Medicine, Chinese Academy of Medical Sciences also independently developed the rare cutter restriction enzymes such as Not I and Sfi I to facilitate the analysis of large DNA fragments of human genome, aiming at physical map construction. These early efforts and progress became truly "the spark of a fire" and the human genome research was thus initiated. In the early 1990s, focusing on the total sequencing and annotation of the complete human genome as its core mission, the Human Genome Project (HGP) was initiated under the leadership of the U.S.A. However, the initial response in China was, instead, to participate in the International Rice Genome Project led by Japan. The reasons behind were obvious. First of all, for China, the largest developing country of the world, food security is of the primary concern and rice is the major staple food for Chinese people. Second, rice, a diploid crop, with its relatively small genome size (about 400 Mb), is a nice model of the monocotyledon plants. Third, over the years, the Chinese scientists had accumulated a great deal of experiences in the basic and applied research of rice, and achieved significant progress in rice breeding and physiology studies, particularly, for the hybrid rice, a model of "Green Revolution". Inspired by these ideas, both the central and the Shanghai municipal governments supported the DNA sequencing expert HONG Guo-Fan, who just returned back to China from Sanger's laboratory, to initiate the rice genome project in 1992 and the Chinese efforts in rice genome sequencing and research were thus, set out on its long journey. Meanwhile, the far-sighted Chinese medical geneticists were still promoting the initiation of a human genome project in China. Academician WU Min, at that time, the director of the Department of Life Sciences, National Natural Science Foundation of China (NSFC), strongly recommended the NSFC committee to initiate some major projects for human genome research. The academician LIANG Dong-Cai, Deputy Director of the NSFC Committee and of the Department of Life Sciences, supported his efforts and thus, the first major human genome project in China was funded to study the genetic variations among the 56 Chinese nationalities. Meanwhile, the Chinese scientists working in the field of medical genetics gradually accepted the concept of genomics, and by applying the genomics technology, they carried out a series of research and made significant breakthroughs in the study and identification of disease associated genes, particularly the cloning and identification of genes related to leukaemia, solid tumours (including liver cancer, colorectal cancer and nasopharyngeal cancer) and genetic diseases (such as deafness). Furthermore, substantial progresses were made in the development of technologies for human genome genotyping and genetic polymorphism detection, as well as for expressed sequence tag (EST) and full-length cDNA cloning and sequencing. All these achievements greatly strengthened the Chinese scientists' confidence and encouraged them to further explore the human genome. On the other hand, they made people perceive and appreciate the Chinese human genetic resources, for their abundance in population (more than 1 billion) with 56 nationalities and numerous relatively isolated ethnic groups. If we actively collect and utilize the resources with intelligence in research, along with the HGP, we will be able to and obligatory to make great contributions to the course of human health, especially to the oriental people for the medical purpose. With this scientific and historical background, in July 1997, the academician TAN Jia-Zhen petitioned the central government, appealing for the protection of the Chinese genetic resources, and proposed to establish the national human genome centre to speed up the human genome research in China. This petition attracted great attention from the Party Central Committee and the State Council. JIANG Ze-Min, the General Secretary of the Party and the President of the People's Republic of China, wrote: "One, who did not think far enough ahead, inevitably may have trouble right-a-way. We have to cherish our genetic resources." Thus, the Shanghai Human Genome Research Center, co-sponsored by the Ministry of Science and Technology, Shanghai Municipal Government, Pudong District, Zhangjiang High-Tech Park, and six research institutions in Shanghai, was founded on March 4, 1998. On October 20, 1998, the centre was officially inaugurated as the Chinese National Human Genome Center at Shanghai (abbreviated as the South Center), thus becoming the first national research centre located in the Zhangjiang Hi-Tech Park of Pudong District. The academician CHEN Zhu has served as the director of the centre ever since, while ZHAO Guo-Ping acted as the executive director of the centre after 2002. At the same time, the National Human Genome Center at Beijing (the North Center) was established with the support of the Ministry of Science and Technology and Beijing Municipal Government, and the academician QIANG Bo-Qin served as the director. The "Huada" (Chinese Giant/Wash U) Genome Center, directed by YANG Huan-Ming, was also established by the Institute of Genetics, CAS. Together with the previously established National Gene Research Center, which was established by the joint efforts of both CAS and the Shanghai Municipality for rice genome research, a basic genomics sequencing and research framework formed in China, with Beijing and Shanghai each equipped with two genome centres. The connection between the human genome project and the rice genome project was greatly promoted, which eventually facilitated the success of the rice genome project. The 9th National Five-Year Plan (1996-2000) witnessed the rise, the struggle and the success of the Chinese genomic research. In the early stage of the 9th Five-Year Plan, the scientific committee of the 863 Program thoroughly assessed the international trend of research related to human health and diseases and promptly determined to set up a "key project" for human genome research, and soon upgraded it as a "major project". The committee set up a "two 1%" goal with respect to the genomic sequencing and the full-length cDNA identification, respectively, and coordinated the efforts of Shanghai and Beijing local government to set up the national human genome research centres for more efficient implementation. After acquiring the "one percent" share of human genome sequencing, the committee, together with CAS, promptly reinforced the support for the sequencing project. Co-ordinately, the National Key Basic Research Program, known as the 973 Program, started a disease genomics project in 1998 led by the academicians CHEN Zhu and QIANG Bo-Qin. The 973 Program continued to fund the project in 2004 under the title of "Systems Biology for the Multi-gene Complex Diseases" coordinated by CHEN Zhu. The Chinese human genome project fully exemplified the "Chinese characteristics". With respect to the project design, besides the above-mentioned "two one percent", it reinforced the research upon disease genomics and focused on the establishment of the disease sample/information collecting network along with the continuous efforts in cloning and identification of disease related genes by employing human genetic resources from China and abroad. The human health oriented functional genomics research, including bioinformatics, transcriptomics, proteomics, structural genomics and other technology platforms, such as model animals, biochip constructions, etc., were all developed along with the human genomic sequencing project in the late 1990s. Making full use of the technology and resource advantages of the human genome research helped to extend the genomic sequencing and related research to plants other than rice, microorganisms (pathogens for medicine and agriculture or important industry bacteria), insects (silkworm) and parasites (Schistosoma japonicum). In 2006, the original and assembled genomic sequence data of S. japonicum was registered in and released from a public bioinformatics database operated by the Shanghai Bioinformation Technology Development Center, for sharing with the international Schistosoma mansoni consortium. This action indicated that genomic information analysis technology had set out an important step forward in merging with the international GeneBank. In summary, although China started late in genomic sequencing, it has caught up with the international wave in functional genomics, and the achievements of which effectively enhanced the life science research and biotechnology development in China. With respect to funding policy and the establishment of platform centres, China adopted the international model initially — organizing grand scientific program/projects and establishing genome centres for implementation. On the other hand, based on the characteristics of funding and administration systems in China, various kinds of operation models for those genome centres were explored in order to encourage all sections of the governmental institutions to offer as much as possible funds through various channels. By adopting these multiple funding patterns under the guidance of the national projects, the Chinese scientists mobilized as much enthusiasm from the society as possible and efficiently integrated the national and local, the governmental and social resources and secured the development of the projects and centres. Take the South Center as an example. During the ten years period since its establishment, in the process of completing a series of international and national key genome projects, the original mixed research team of the centre was tempered, and the abilities of the team members were improved. Meanwhile, influenced by the centre, an array of "omics" and systems biomedicine research centres were gradually set up in the Zhangjiang HiTech Park of Shanghai. Collaborating with these research centres, the South Center has been accomplishing its transformation from a platform technology centre focusing on sequencing and genotyping services to a research centre engaged in the cutting-edge innovation on molecular targets identification and characterization for human health and diseases and the translational research on genomics, molecular genetics and systems biomedicine. Meanwhile, through the constant improvement of its comprehensive competitiveness in science and technology innovation, the service function of this systems biology research platform is becoming more substantial, and the centre continues to promote the formation and transformation of intellectual property based on the biomedicine research achievements. In fact, within the past ten years, the progress of genomics in China was a sort of frog leap development in terms of scale, quality, interdisciplinary, organization and international collaboration. The genomics research of human and rice, the two national major scientific projects, together with a series of genomic sequencing and functional genomics analyses, constitutes an unprecedented development in life science research and biotechnology development in China. For decades, particularly from the early 1950s to the 1970s, genetics and molecular genetics were sort of lagging in China, largely due to the influences of Lysenkonism in the 1950-1960s and then the hit by "cultural revolution" in the 1960-1970s. Fortunately, in this difficult period, with the cooperation of Chinese biologists and chemists, protein and nucleic acid chemistry gained a rapid development. The chemical synthesis and 3D structure determination of bovine insulin and the chemical synthesis of yeast alanine-tRNA were land marker achievements recorded in the scientific history. In contrast to the situation in China, from the 1960s to the 1980s, life science worldwide was led by genetics and molecular biology, i.e., studying DNA/RNA and the flow of genetic information (central dogma). In China, these disciplines were severely hampered, with few scientists such as Prof. TAN Jia-Zhen to be the only leading scientist to defend Morgan's theory for a long time. Therefore, China's life science was largely behind the world development trend for decades. However, in the early 1990s, with the incoming "scientific spring", Chinese life scientists grasped the historical opportunity of HGP to catch up with the world cutting-edge life science and realized a frog leap forward. For the first time, the concept of "big science" was introduced into the Chinese life science community thanks to HGP. The "big sciences" are grand scientific research programs guided with a comprehensive and long-term objective to tackle the major scientific problems related to the development of human and human society. They aimed to gather important scientific data and to make significant scientific discoveries with the aid of multi-disciplinary studies and integrated technologies. A strong link between big and small sciences was set up, in that in the genomic era, no body doing small science related to molecular biology, biochemistry and cell biology won't benefit from the dataset generated by human (and other) genomic studies. For instance, just in Shanghai, biologists engaging in molecular biology studies of mammalian reproductive system, signal transduction, immunology, microbiology, central nerve system, genetic evolution, leukaemia and pathogenesis, were all somehow involved in genomics work to certain extent. The rise of other molecular "omics" further strengthened the linkage of "big science" and "small science". For such a tremendous impact of this linkage upon life science research and the development of biotechnology, it is truly a revolution. Human genome study in China initiated a new phase of interdisciplinary in the history of life science in China. The rise of genomics relied on its integration with other academic disciplines, particularly in the following three areas. First, the integration with technology science has caused several rounds of revolution in DNA sequencing technology in the past 40 years, which directly led the first sequencing trial of 4 bases of the λ phage cosmid to the current program of sequencing the genomes of a thousand individuals. Second, the integration with computational science and computer technology brought about bioinformatics, which supported the system of data collection, administration, annotation, distribution, and services for genome researches; and the technology platform for data analysis, was also thus established. Third, the integration with mathematics and statistics led to the rise of computational biology, which makes full use of the genomic data and the data generated by other "omics" and then, analyzes them with various kinds of biological data. It provides experimental scientists with hypotheses/models for systems biology research. Actually, mainly promoted by bioinformatics and computational biology, laws of a complex life system can now be deciphered and understood. Human genomic research, with the magnitude of "big science "and "big project" and unprecedented dynamics of development, facilitated, in an extraordinary way, the domestic and international collaboration. HGP in China set a good example for "liberation of mind" in the life science fields. It makes the Chinese biologists to understand what the meaning of "leading the scientific frontier" is and what the "national strategic demand" is. It also inspired the Chinese biologists to challenge the important scientific problems and to participate in the international collaboration and competition. What's more, it teaches the Chinese biologists how to organize scientific teams for major scientific research projects and how to efficiently coordinate the nation-wide research efforts. In the early 1990s, in the mind of the leaders of Chinese human genome research, a consensus had been reached, that is: "In the next century, China will be one of the leading countries in genomics and life science. If we do not start the genomics program today, we are going to lose the right of voice in 10 years. Though we start from small, we shall harvest huge." With ten years of persistent struggle and hard working, we keep our words and have mostly realized these objectives. To recall the history is for a better development in the future. After the completion of the genomic sequencing and the HapMap project, the international HGP has entered an assault-fortified position aiming at studying the genetic mechanisms of human diseases and other phenotypes. The initiation of HGP is due to the lesson learnt from the failure of the cancer project in the Kennedy era of the 1960s, while the success of HGP also depends on its influence upon tackling cancer and other complex human diseases. Meanwhile, facilitated by the strategic plan of big sciences, the innovation of science and technology and their industrialization, as well as the fast progress in interdisciplinary studies such as bioinformatics, have prepared the ground for a new "great frog leap". Some of the mini-reviews published in this issue analyze the future trend of genomics research and its scientific impact based on the technical perspectives of genomic sequencing, genotyping and functional genomics. While the others present the significant change of research strategy and technology brought in by the HGP with respect to liver cancer (hepatocarcinoma), immunology, and medical, environmental and industrial microbiology. These reviews reflect the progress we have achieved, showing that, compared with the situation ten years ago, our research capability, technology experience, and academic intelligence have all been significantly improved. Meanwhile, we are confronted with more difficult challenges than ten years ago. If we can learn from the past experience, focus on a correct direction, move forward bravely but with caution, carefully organize and integrate the research teams, improve the management with both democracy and discipline, and work hard to explore the scientific truth, we shall be able to make faster and greater progress. On the other hand, if we arrogantly enjoy the past but ignore the new challenge, or underestimate our capabilities and feel afraid of innovation, it is possible that we may miss the good opportunities, as said in this old Chinese proverb, "Ninety miles is only half way of a hundred-mile journey". Confucius once said: "The passage of time is just like the flow of the River, which goes on day and night, for ever". The past glories are the momentum for our new journey, while the lessons of the past may teach us to be smarter. China, a developing socialist country rising from a hundred years of weakness and poverty, needs genomics to make historic contributions to the rejuvenation of the nation. Chen Zhu and Zhao Guo-Ping Shanghai Key Laboratory of Disease and Health Genomics The Chinese National Human Genome Center at Shanghai The People's Republic of China Reference: Sci China Ser C-Life Sci., Jan. 2008, vol. 52, no. 1, pp.2-6 doi: 10.1007/s11427-009-0016-5 See also: Science Key to China's Development CellNEWS - Thursday, 16 October 2008 Progress of China's Stem Cell Research CellNEWS - Tuesday, 05 August 2008 China Becoming Worlds Powerhouse in Science CellNEWS - Saturday, 02 August 2008 International Human Genome Project Launched CellNEWS - Wednesday, 23 January 2008 China's Biotech Industry CellNEWS - Monday, 07 January 2008 First Complete Asian Genome CellNEWS - Friday, 12 October 2007 ......... ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html

---

Novel Types of Stem Cells Generated

Breakthrough may offer opportunity for expanding research, drug discovery Thursday, 18 December 2008 The study, which appears in the December 18 online version of Cell Stem Cell and the January 2009 print edition of the journal, provides proof of principle that alternative sources of stem cells can be created. The team, which included scientists from Scripps Research, Peking University, and the University of California, San Diego, conducted the studies to establish novel rat induced pluripotent stem cell lines (riPSCs) and human induced pluripotent stem cell lines (hiPSCs) by using a specific cocktail of chemicals combined with genetic reprogramming, a process whereby an adult cell is returned to its early embryonic state. Pluripotency refers to the ability of a cell to develop into each of the more than 200 cell types of the adult body. Mimicking Human Physiology Scientists genetically engineer embryonic stem cells to create mouse models that contain the engineered genes — so-called transgenic animals — in the hope of applying the knowledge gained from studying such mice to benefit humans. Although using mouse pluripotent embryonic stem cells has been the standard since these cells were first derived in 1981, researchers have long wanted to apply such powerful techniques to other animal species to help the study of human physiology and disease. The major advantage of using other animal species, such as rats, is that the physiology of these animals can better mimic human physiology, for example, in studies of metabolic and neurological diseases. The size of other animals also is an advantage because larger organs and tissues are easier to work with. Because of these benefits, scientists have created transgenic animals from species other than mice, but the lack of pluripotent stem cells from these species and the tedious and imprecise techniques currently available has made the process difficult. "Mouse models created with pluripotent embryonic stem cells are wonderful tools for understanding the fundamental biology of genes," says Sheng Ding, Ph.D., an associate professor in the Scripps Research Department of Chemistry who was senior author of the study with Peking University investigator Hongkui Deng, Ph.D. "But in some important ways these models are less than ideal. Our demonstrated technologies will enable unprecedented and broad applications for better creating animal models from other species." Novel and More Robust Human Pluripotent Stem Cells In another closely related aspect of this work, Ding has also shown that a new kind of human pluripotent stem cell can now be created using the same chemical and reprogramming methods used to create the rat pluripotent stem cells. Human pluripotent stem cells hold promise for modelling human development and disease, testing drugs, and providing unlimited functional cells for cell replacement therapy. "Recent studies have found, however, that conventional human embryonic stem cells represent a different pluripotent cell type and are not the counterpart of the conventional, and most useful, mouse embryonic stem cells," Ding says. The issue is that pluripotent stem cells can be represented by cells from two distinct stages of embryonic development — the early pre-implantation blastocyst stage and the later post-implantation epiblast stage. Today, conventional mouse embryonic stem cells represent the pre-implantation stage pluripotent cells, and human embryonic stem cells appear to represent later post-implantation stage pluripotent cells. Early- and late-stage cells have very different properties. For example, they respond differently to the same signals given to stem cells to differentiate into specific types of cells. The pre-implantation stage of cells will differentiate into one type of cell, while post-implantation stage of cells will turn into other types of cells. Their propensity toward specific cell types and growth properties are also different. The novel human pluripotent cells created by the scientists appear to represent the early stage of pluripotent cells — closer to well researched conventional mouse embryonic stem cells — and grow with better properties. "The different behaviours of the pre- and post-implantation pluripotent stem cells means that findings from research done on mouse embryonic stem cells are often not translatable to work done on human embryonic stem cells," Ding says. "With our new human pluripotent stem cells, we again have proof of principle that human stem cells can be created that are similar to mouse embryonic stem cells. The knowledge gained from mouse studies, therefore, will be more directly translatable to human cells, offering an advantage in biomedical research." ......... ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html

---

Science Key to China's Development

Chinese Premier Wen Jiabao Sees Science as Key to Development Thursday, 16 October 2008 During a two-hour meeting with the editor-in-chief of the journal Science, Chinese Premier Wen Jiabao expressed hope for increasing investment in basic research, reducing energy consumption by 4 percent annually as economic gains continue, improving food safety, and leveraging science to help the poor. Wen's conversation with Bruce Alberts of Science is being published in the journal's 17 October 2008 edition. An editorial written by Wen, plus a news article on science and technology in China, also will appear in a forthcoming issue of Science, which is published by the non-profit American Association for the Advancement of Science (AAAS). "In recent years, we have continuously increased the level of support" for basic research, Wen told Alberts, describing fundamental scientific investigations as "the wellspring and driving force" of innovation. "But I think [China's investment in basic research] is still insufficient." China's Ministry of Science and Technology has reported that 5 percent of the nation's total investment in science is being spent on basic research, according to Alberts, a professor of biochemistry and biophysics at the University of California, San Francisco. By comparison, the U.S. National Science Foundation (NSF) has reported that 17.5 percent of the United States' total investment in science was being spent on basic research in 2007. However, scientific achievement by Chinese scientists and engineers has turned sharply upward in recent years, based on scholarly journal articles and patents. In addition, Alberts said after returning to Washington, D.C. that he was extremely impressed by the high calibre of students he met at Tsinghua and Peking universities. Among 500,000 young people who took a national university entrance examination in one particular province, for example, only 70 were accepted, according to a student who spoke with Alberts during his trip. Alberts, visiting Beijing to deliver lectures at the Chinese Academy of Medical Sciences and Tsinghua University, joined Science Asia News Editor Richard Stone for the rare personal meeting with the Chinese Premier and Chen Zhu, China's Minister of Health. Chen was instrumental in arranging the meeting, which was also attended by Science contributing correspondent Hao Xin. Remarks by Wen — a professional geologist who is in charge of China's government and works closely with President Hu Jintao — "clearly reveal his passion for both science and technology, as well as his recognition of their central importance to society," Alberts said. For example, when asked about the recent tainted-milk crisis in China, Wen said that both the producers and the government must accept responsibility for preventing foods from being tainted in the future. "We feel great sorrow about this milk incident," he said. "I once again solemnly emphasize that it is absolutely impermissible to sacrifice people's lives and health in exchange for temporary economic development." All foods must meet international standards, and in particular, exported foods must meet the standards of importing countries, Wen said. The Ministry of Health has now been assigned central oversight of food safety in China, he added. Wen also acknowledged China's challenges in moving toward more environmentally friendly practices, and he promised that the country will continue to make improvements. "We have established a goal, that is in future development, our [Gross Domestic Product] growth every year must be accompanied by a 4 percent decrease in energy consumption," he said, "and a 2 percent reduction in [chemical oxygen demand] and sulphur dioxide emissions every year." Noting that China has been an industrial nation only for several decades, he nonetheless added that "we will now begin to shoulder our due responsibilities" for protecting the environment. China's coal production currently exceeds 2.5 billion tons per year. "This kind of huge consumption of energy, especially non-renewable fossil fuel, will not be sustainable," Wen said. Alberts congratulated Wen on his country's recent successful space mission. The Science editor-in-chief further proposed that science and science diplomacy can be important tools for helping to ease political tensions between nations because scientists all over the world share common goals to improve human welfare. Wen agreed. "Exchanges and collaborations between scientists can help promote exchange and co-operations in economic and social realms between countries," he said. "More scientific language and less diplomatic rhetoric may make this world even better." Wen applied his scientific training when he was called upon to respond to the tragic 12 May 2008 Wenchuan earthquake. In his conversation with Alberts, Wen described his four priorities for responding to the disaster and helping to prevent earthquake damage in the future. The first priority was to help people, and Wen said that 80,000 were rescued from the earthquake rubble. He described his second priority as improving the monitoring of aftershocks. A third priority was to prevent "quake lakes" from bursting, and Wen said that the Tangjiashan quake lake, containing 300 million cubic meters of water and endangering Mianyang, is being successfully managed. Wen described his fourth priority for disaster recovery as preventing disease in the hardest hit regions. Alberts' interview with Wen also covered China's "scientific outlook on development." Wen explained that there are several fundamental principles at the heart of China's science-based efforts to improve people's lives and the country's economy. Specifically, he said that any plan for China's progress should put people first, by seeking to increase material as well as cultural prosperity. In addition, Wen advocated "comprehensive development," which he described as including the integration of economic and political reform, or progress but also traditional Chinese culture. He further said that China's efforts will seek to resolve disparities between rich and poor, and balance development within the agricultural, industry and service sectors of the economy. Finally, he said that China will work toward sustainable development that addresses the inherent challenge of limited resources to support a population of 1.3 billion. Wen noted that innovation "needs to start with children," who must learn independent thinking and creative problem-solving. He also emphasized that students must cultivate scientific ethics and "uphold the truth, seek truth from facts, be bold in innovation and tolerant of failure." Wen promised to "hold fast to the policy of opening up to the outside world." Both Wen and Alberts discussed the importance of science education for achieving economic progress, life-changing scientific advances and better understanding between nations. Coincidentally, the visit between Wen and Alberts took place on the 30th anniversary of the first delegation of AAAS to China, as well as the first anniversary of the opening of Science's Beijing bureau. The meeting also occurred in tandem with two other key AAAS activities in China. Past AAAS President Peter Raven of the Missouri Botanical Garden had visited China at the same time to deliver the first-ever AAAS-Chinese Academy of Sciences Distinguished Lectureship on Sustainability. Tom Wang, AAAS director for international cooperation who also serves as deputy director for the new AAAS Center for Science Diplomacy, joined Raven on his trip. Catherine Matacic, who runs the EurekAlert! Chinese Web site at AAAS, was in Beijing, too, to coordinate what was believed to be the first China-based press conference related to a Science paper. The Science press conference in Beijing focused on a study by Chinese scientists who concluded that genetically engineered cotton had effectively reduced populations of cotton bollworms, and also seemed to benefit other crops. The study, by Kongming Wu, Yanhui Lu and Hongqiang Feng of the Chinese Academy of Agricultural Sciences, was the latest example of outstanding China-authored research appearing in Science. Worldwide, Science editors receive some 12,000 submissions each year. Between 7 percent and 8 percent of those submissions, or 840 to 960 articles ultimately are accepted for publication, following rigorous peer review. In 2007, Science published approximately 30 articles with Chinese authors or co-authors, according to Science Deputy Managing Editor Brooks Hanson. Alberts, president emeritus of the U.S. National Academy of Sciences who served as chair of the National Research Council from 1983 until 2005, has special interests in science education and international scientific cooperation. "Bruce Alberts joined AAAS and Science after many years of international scientific leadership. His activities have resulted in cooperative relationships with an array of influential scientists, engineers and leaders in other countries," said Alan I. Leshner, chief executive officer of AAAS and executive publisher of Science. "And one of those connections was able to help facilitate the meeting with the Chinese premier. We also were very fortunate to have an award-winning reporter like Richard Stone on staff who has become very well respected in the Chinese scientific and journalism communities, and thus could help make the right connections for this unique interview." Since opening the Science Beijing bureau in October 2007, Stone has covered major events such as the devastating earthquake. His reporting has ensured that a steady stream of news and feature stories from China appear in Science. He also has sought to raise Science's profile in China by appearing as a guest commentator on China's English-language TV station, China Central Television (CCTV)-9. Stone described the meeting with Wen at the government leaders' compound in the heart of Beijing, Zhongnanhai, as a thrill and an honor. "I can't imagine a better way to cap our first year in China," he said. In 2007, AAAS Chief International Officer Vaughan Turekian and Wang helped to formalize agreements with two of China's leading scientific organizations, outlining plans for collaboration related to publishing, science education, sustainability, science policy, and opportunities for women scientists and engineers. The AAAS agreements with the Chinese Academy of Sciences and the China Association for Science and Technology call for cooperative efforts to translate and disseminate educational materials and high-impact Science papers, among other efforts. "This meeting demonstrated the seriousness that China's most senior officials place on science and technology as a critical driver to their broader development plans," Turekian said. "There are only a handful of leaders in the world that would commit this sort of time to meet with a foreign scientist. AAAS and Science were grateful for the opportunity." About the American Association for the Advancement of Science: The American Association for the Advancement of Science (AAAS) is the world's largest general scientific society, and publisher of the journal, Science (www.sciencemag.org). AAAS was founded in 1848, and includes some 262 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world, with an estimated total readership of one million. The non-profit AAAS (www.aaas.org) is open to all and fulfils its mission to "advance science and serve society" through initiatives in science policy; international programs; science education; and more. Reference: China's Scientist Premier Science 17 October 2008: 362-364, DOI: 10.1126/science.322.5900.362 See also: Chinese premier expounds on "Scientific Outlook on Development" Xinhua - 2008-10-18 ......... ZenMaster

---

For more on stem cells and cloning, go to CellNEWS at http://cellnews-blog.blogspot.com/ and http://www.geocities.com/giantfideli/index.html

---

I Love the Olympic's! III

I Love the Olympic's! Tuesday, 19 August 2008

---

Dancing in the Water outside the WaterCube!

---

ZenMaster

I Love the Olympic's! II

I Love the Olympic's! Tuesday, 19 August 2008

---

With Swedish supporters...

---

ZenMaster

I Love the Olympic's! I

I Love the Olympic's! Saturday, 16 August 2008

---

My friend in Beijing...

---

ZenMaster