First Embryonic Stem Cells Derived from Rats I

Finding represents major breakthrough for biomedical research Thursday, 25 December 2008 Researchers at the University of Southern California (USC) have, for the first time in history, derived authentic embryonic stem (ES) cells from rats. This breakthrough finding will enable scientists to create far more effective animal models for the study of a range of human diseases. The research will be published in the Dec. 26 issue of the journal Cell. "This is a major development in stem cell research because we know that rats are much more closely related to humans than mice in many aspects of biology. The research direction of many labs around the world will change because of the availability of rat ES cells," says Qi-Long Ying, Ph.D., assistant professor of Cell and Neurobiology at the Keck School of Medicine of USC, researcher at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, and the study's principal investigator. The finding brings scientists much closer to creating "knockout" rats — animals that are genetically modified to lack one or more genes — for biomedical research. By observing what happens to animals when specific genes are removed, researchers can identify the function of the gene and whether it is linked to a specific disease. "Without ES cells it is impossible to perform precise genetic modifications for the creation of the disease model we want," he says. "The availability of rat ES cells will greatly facilitate the creation of rat models for the study of different human diseases, such as cancer, diabetes, high blood pressure, addiction and autoimmune diseases." Ying, a native of China, notes that this breakthrough research occurred during 2008, the Chinese year of the rat. Embryonic stem cells are derived from a group of cells called the inner cell mass in a very early stage embryo. ES cells provide researchers with a valuable tool to address fundamental biological questions, because they enable scientists to study how genes function, and to develop animals with conditions that mimic important human diseases. Martin Evans of Cardiff University, UK, who was last year awarded the Nobel Prize in Medicine or Physiology, established the first ES cell lines from mice in 1981. Researchers have long been working on establishing rat ES cells, but faced technical hurdles because the conventional methods developed for the derivation of mouse cells did not work in rats. Building on recent research into how ES cells are maintained, the USC researchers found that rat ES cells can be efficiently derived and grown in the presence of the "3i medium," which consists of molecules that inhibit three specific gene signalling components (GSK3, MEK and FGF receptor kinase). This approach insulates the stem cell from signals that would normally cause it to differentiate, or turn into specialized types of body cells. By blocking these signals, Ying and colleagues found that stem cells from rats, which have previously failed to propagate at all, could be grown indefinitely in the laboratory in the primitive embryonic state. An accompanying study led by researchers at the University of Cambridge, UK, reported similar findings, independently verifying that authentic ES cells can be established from rats. Both papers will be published in the upcoming issue of Cell. "The development of rat embryonic stem cells, long sought by researchers around the world, is a major advance in biomedical science," says Martin Pera, Ph.D., director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. "These new stem cell lines will make a huge contribution to basic and applied research and drug development, by providing a technology platform for facile genetic manipulation of a mammalian species that is widely used in academic and industrial labs studying physiology, pathology and pharmacology." Until now, authentic ES cells have never been established from humans or animals other than mice. This new key understanding into how ES cells are maintained in culture may eventually enable scientists to establish real ES cell lines from a number of other mammals, which could have significant implications for organ transplantations and the development of drug therapies, Ying says. Researchers at USC are currently working on generating the first gene knockout rat through ES cell-based technologies. "If our work is feasible it is likely that many labs will follow up to generate different types of gene knockout rat models," he says. "This will have a major impact on the future of biomedical research." References: Germline Competent Embryonic Stem Cells Derived from Rat Blastocysts Ping Li, Chang Tong, Ruty Mehrian-Shai, Li Jia, Nancy Wu, Youzhen Yan, Eric N. Schulze, Houyan Song, Chih-Lin Shieh, Martin F. Pera, Qi-Long Ying Cell, Volume 135, Issue 7, 1299-1310, doi:10.1016/j.cell.2008.12.006 Capture of Authentic Embryonic Stem Cells from Rat Blastocysts Mia Buehr, Stephen Meek, Kate Blair, Jian Yang, Janice Ure, Jose Silva, Renee McLay, John Hall, Qi-Long Ying, Austin Smith Cell, Volume 135, Issue 7, 1287-1298, doi:10.1016/j.cell.2008.12.007 First ESCs Derived from Rats II CellNEWS - Thursday, 25 December 2008 ......... ZenMaster

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Colouring the Biomedical Research gets the Nobel Prize in Chemistry 2008

Nobel Prize in Chemistry 2008 is lighting up biomedical research Wednesday, 08 October 2008 This years Nobel Prize in Chemistry goes to: Osamu Shimomura, Marine Biological Laboratory (MBL), Woods Hole, MA, USA, Martin Chalfie, Columbia University, New York, NY, USA, Roger Y. Tsien, University of California, San Diego, CA, USA "for the discovery and development of the green fluorescent protein, GFP"

for colouring the biomedical research!

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Zebra fish glowing green and red.

GloFish. Courtesy of www.glofish.com.

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Glowing proteins – a guiding star for biochemistry The remarkable brightly glowing green fluorescent protein, GFP, was first observed in the beautiful jellyfish, Aequorea victoria in 1962. Since then, this protein has become one of the most important tools used in contemporary bioscience. With the aid of GFP, researchers have developed ways to watch processes that were previously invisible, such as the development of nerve cells in the brain or how cancer cells spread. Tens of thousands of different proteins reside in a living organism, controlling important chemical processes in minute detail. If this protein machinery malfunctions, illness and disease often follow. That is why it has been imperative for bioscience to map the role of different proteins in the body. This year's Nobel Prize in Chemistry rewards the initial discovery of GFP and a series of important developments which have led to its use as a tagging tool in bioscience. By using DNA technology, researchers can now connect GFP to other interesting, but otherwise invisible, proteins. This glowing marker allows them to watch the movements, positions and interactions of the tagged proteins. Researchers can also follow the fate of various cells with the help of GFP: nerve cell damage during Alzheimer's disease or how insulin-producing beta cells are created in the pancreas of a growing embryo. In one spectacular experiment, researchers succeeded in tagging different nerve cells in the brain of a mouse with a kaleidoscope of colours. The story behind the discovery of GFP is one with the three Nobel Prize Laureates in the leading roles: Osamu Shimomura first isolated GFP from the jellyfish Aequorea victoria, which drifts with the currents off the west coast of North America. He discovered that this protein glowed bright green under ultraviolet light. Martin Chalfie demonstrated the value of GFP as a luminous genetic tag for various biological phenomena. In one of his first experiments, he coloured six individual cells in the transparent roundworm Caenorhabditis elegans with the aid of GFP.

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Roger Y. Tsien, Howard Hughes Medical Institute at the University of California, San Diego. Credit: Joe Toreno for HHMI.

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Roger Y. Tsien contributed to our general understanding of how GFP fluoresces. He also extended the colour palette beyond green allowing researchers to give various proteins and cells different colours. This enables scientists to follow several different biological processes at the same time. Osamu Shimomura, Japanese citizen. Born 1928 in Kyoto, Japan. Ph.D. in organic chemistry 1960 from Nagoya University, Japan. Professor emeritus at Marine Biological Laboratory (MBL), Woods Hole, MA, USA and Boston University Medical School, MA, USA. Martin Chalfie, US citizen. Born 1947, grew up in Chicago, IL, USA. Ph.D. in neurobiology 1977 from Harvard University. William R. Kenan, Jr. Professor of Biological Sciences at Columbia University, New York, NY, USA, since 1982. Roger Y. Tsien, US citizen. Born 1952 in New York, NY, USA. Ph.D. in physiology 1977 from Cambridge University, UK. Professor at University of California, San Diego, La Jolla, CA, USA, since 1989. ......... ZenMaster

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Passion for Symmetry Gets Nobel Prize in Physics 2008

Three Japanese Researchers Gets the Nobel Prize in Physics 2008 Tuesday, 07 October 2008 Goes to three Japanese researchers, Yoichiro Nambu, Makoto Kobayashi, Toshihide Maskawa. Yoichiro Nambu, Enrico Fermi Institute, University of Chicago, Chicago, IL, USA, with one half of the Prize: "for the discovery of the mechanism of spontaneous broken symmetry in subatomic physics" and the other half jointly to Makoto Kobayashi, High Energy Accelerator Research Organization (KEK), Tsukuba, Japan, and Toshihide Maskawa, Yukawa Institute for Theoretical Physics (YITP), Kyoto University Kyoto, Japan "for the discovery of the origin of the broken symmetry which predicts the existence of at least three families of quarks in nature" See also: The Nobel Prize in Physics 2008 Unravelling the hidden symmetries of nature The Royal Swedish Academy of Sciences

Passion for symmetry The fact that our world does not behave perfectly symmetrically is due to deviations from symmetry at the microscopic level. As early as 1960, Yoichiro Nambu formulated his mathematical description of spontaneous broken symmetry in elementary particle physics. Spontaneous broken symmetry conceals nature’s order under an apparently jumbled surface. It has proved to be extremely useful, and Nambu’s theories permeate the Standard Model of elementary particle physics. The Model unifies the smallest building blocks of all matter and three of nature’s four forces in one single theory. The spontaneous broken symmetries that Nambu studied, differ from the broken symmetries described by Makoto Kobayashi and Toshihide Maskawa. These spontaneous occurrences seem to have existed in nature since the very beginning of the universe and came as a complete surprise when they first appeared in particle experiments in 1964. It is only in recent years that scientists have come to fully confirm the explanations that Kobayashi and Maskawa made in 1972. It is for this work that they are now awarded the Nobel Prize in Physics. They explained broken symmetry within the framework of the Standard Model, but required that the Model be extended to three families of quarks. These predicted, hypothetical new quarks have recently appeared in physics experiments. As late as 2001, the two particle detectors BaBar at Stanford, USA and Belle at Tsukuba, Japan, both detected broken symmetries independently of each other. The results were exactly as Kobayashi and Maskawa had predicted almost three decades earlier. A hitherto unexplained broken symmetry of the same kind lies behind the very origin of the cosmos in the Big Bang some 14 billion years ago. If equal amounts of matter and antimatter were created, they ought to have annihilated each other. But this did not happen, there was a tiny deviation of one extra particle of matter for every 10 billion antimatter particles. It is this broken symmetry that seems to have caused our cosmos to survive. The question of how this exactly happened still remains unanswered. Perhaps the new particle accelerator LHC at CERN in Geneva will unravel some of the mysteries that continue to puzzle us.

• Yoichiro Nambu, US citizen. Born 1921 in Tokyo, Japan. D.Sc. 1952 at University of Tokyo, Japan. Harry Pratt Judson Distinguished Service Professor Emeritus at Enrico Fermi Institute, University of Chicago, IL, USA.
• Makoto Kobayashi, Japanese citizen. Born 1944 in Nagoya, Japan. Ph.D. 1972 at Nagoya University, Japan. Professor Emeritus at High Energy Accelerator Research Organization (KEK), Tsukuba, Japan.
• Toshihide Maskawa, Japanese citizen. Born 1940. Ph.D. 1967 at Nagoya University, Japan. Professor Emeritus at Yukawa Institute for Theoretical Physics (YITP), Kyoto University, Japan.

......... ZenMaster

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Virus Work Awarded in 2008 Nobel Prize in Physiology or Medicine

HPV and HIV virus work avarded this year Monday, 06 October 2008 Harald zur Hausen, at the German Cancer Research Centre in Heidelberg, Germany get half of the Nobel Prize in Physiology or Medicine 2008: "for his discovery of human papilloma viruses causing cervical cancer". See also in CellNEWS: Vaccine Makes Cervical Cancer Control Feasible Thursday, 28 August 2008 The other half is scared by Françoise Barré-Sinoussi and Luc Montagnier, Institut Pasteur Paris, France, for their discovery of HIV/AIDS virus: "for their discovery of human immunodeficiency virus" .

See also: Dispute behind Nobel Prize for HIV research French researchers win for virus discovery; controversial scientist shunned MSNBC - October 6, 2008 This year's Nobel Prize awards discoveries of two viruses causing severe human diseases. Harald zur Hausen went against current dogma and postulated that oncogenic human papilloma virus (HPV) caused cervical cancer, the second most common cancer among women. He realized that HPV-DNA could exist in a non-productive state in the tumours, and should be detectable by specific searches for viral DNA. He found HPV to be a heterogeneous family of viruses. Only some HPV types cause cancer. His discovery has led to characterization of the natural history of HPV infection, an understanding of mechanisms of HPV-induced carcinogenesis and the development of prophylactic vaccines against HPV acquisition. Françoise Barré-Sinoussi and Luc Montagnier discovered human immunodeficiency virus (HIV). Virus production was identified in lymphocytes from patients with enlarged lymph nodes in early stages of acquired immunodeficiency, and in blood from patients with late stage disease. They characterized this retrovirus as the first known human lentivirus based on its morphological, biochemical and immunological properties. HIV impaired the immune system because of massive virus replication and cell damage to lymphocytes. The discovery was one prerequisite for the current understanding of the biology of the disease and its antiretroviral treatment. Discovery of human papilloma virus causing cervical cancer Against the prevailing view during the 1970s, Harald zur Hausen postulated a role for human papilloma virus (HPV) in cervical cancer. He assumed that the tumour cells, if they contained an oncogenic virus, should harbour viral DNA integrated into their genomes. The HPV genes promoting cell proliferation should therefore be detectable by specifically searching tumour cells for such viral DNA. Harald zur Hausen pursued this idea for over 10 years by searching for different HPV types, a search made difficult by the fact that only parts of the viral DNA were integrated into the host genome. He found novel HPV-DNA in cervix cancer biopsies, and thus discovered the new, tumourigenic HPV16 type in 1983. In 1984, he cloned HPV16 and 18 from patients with cervical cancer. The HPV types 16 and 18 were consistently found in about 70% of cervical cancer biopsies throughout the world. Importance of the HPV discovery The global public health burden attributable to human papilloma viruses is considerable. More than 5% of all cancers worldwide are caused by persistent infection with this virus. Infection by the human papilloma virus is the most common sexually transmitted agent, afflicting 50-80% of the population. Of the more than 100 HPV types known, about 40 infect the genital tract, and 15 of these put women at high risk for cervical cancer. In addition, HPV is found in some vulval, penile, oral and other cancers. Human papilloma virus can be detected in 99.7% of women with histologically confirmed cervical cancer, affecting some 500,000 women per year. Harald zur Hausen demonstrated novel properties of HPV that have led to an understanding of mechanisms for papilloma virus-induced carcinogenesis and the predisposing factors for viral persistence and cellular transformation. He made HPV16 and 18 available to the scientific community. Vaccines were ultimately developed that provide ≥95 % protection from infection by the high risk HPV16 and 18 types. The vaccines may also reduce the need for surgery and the global burden of cervical cancer.

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Discovery of HIV Following medical reports of a novel immunodeficiency syndrome in 1981, the search for a causative agent was on. Françoise Barré-Sinoussi and Luc Montagnier isolated and cultured lymph node cells from patients that had swollen lymph nodes characteristic of the early stage of acquired immune deficiency. They detected activity of the retroviral enzyme reverse transcriptase, a direct sign of retrovirus replication. They also found retroviral particles budding from the infected cells. Isolated virus infected and killed lymphocytes from both diseased and healthy donors, and reacted with antibodies from infected patients. In contrast to previously characterized human oncogenic retroviruses, the novel retrovirus they had discovered, now known as human immunodeficiency virus (HIV), did not induce uncontrolled cell growth. Instead, the virus required cell activation for replication and mediated cell fusion of T lymphocytes. This partly explained how HIV impairs the immune system since the T cells are essential for immune defence. By 1984, Barré-Sinoussi and Montagnier had obtained several isolates of the novel human retrovirus, which they identified as a lentivirus, from sexually infected individuals, haemophiliacs, mother to infant transmissions and transfused patients. The significance of their achievements should be viewed in the context of a global ubiquitous epidemic affecting close to 1% of the population. Importance of the HIV discovery Soon after the discovery of the virus, several groups contributed to the definitive demonstration of HIV as the cause of acquired human immunodeficiency syndrome (AIDS). Barré-Sinoussi and Montagnier's discovery made rapid cloning of the HIV-1 genome possible. This has allowed identification of important details in its replication cycle and how the virus interacts with its host. Furthermore, it led to development of methods to diagnose infected patients and to screen blood products, which has limited the spread of the pandemic. The unprecedented development of several classes of new antiviral drugs is also a result of knowledge of the details of the viral replication cycle. The combination of prevention and treatment has substantially decreased spread of the disease and dramatically increased life expectancy among treated patients. The cloning of HIV enabled studies of its origin and evolution. The virus was probably passed to humans from chimpanzees in West Africa early in the 20th century, but it is still unclear why the epidemic spread so dramatically from 1970 and onwards. Identification of virus−host interactions has provided information on how HIV evades the host’s immune system by impairing lymphocyte function, by constantly changing and by hiding its genome in the host lymphocyte DNA, making its eradication in the infected host difficult even after long-term antiviral treatment. Extensive knowledge about these unique viral host interactions has, however, generated results that can provide ideas for future vaccine development as well as for therapeutic approaches targeting viral latency. HIV has generated a novel pandemic. Never before has science and medicine been so quick to discover, identify the origin and provide treatment for a new disease entity. Successful anti-retroviral therapy results in life expectancies for persons with HIV infection now reaching levels similar to those of uninfected people.

• Harald zur Hausen, born 1936 in Germany, German citizen, MD at University of Düsseldorf, Germany. Professor emeritus and former Chairman and Scientific Director, German Cancer Research Centre, Heidelberg, Germany.
• Françoise Barré-Sinoussi, born 1947 in France, French citizen, PhD in virology, Institut Pasteur, Garches, France. Professor and Director, Regulation of Retroviral Infections Unit, Virology Department, Institut Pasteur, Paris, France.
• Luc Montagnier, born 1932 in France, French citizen, PhD in virology, University of Paris, Paris, France. Professor emeritus and Director, World Foundation for AIDS Research and Prevention, Paris, France.

......... ZenMaster

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