CellNEWS: January 2009

Friday, 30 January 2009

Stem Cell Transplant Reverses Early-stage Multiple Sclerosis

Stem Cell Transplant Reverses Early-stage Multiple Sclerosis Friday, 30 January 2009 Researchers from Northwestern University's Feinberg School of Medicine appear to have reversed the neurological dysfunction of early-stage multiple sclerosis patients by transplanting their own immune stem cells into their bodies and thereby "resetting" their immune systems. "This is the first time we have turned the tide on this disease," said principal investigator Richard Burt, M.D. chief of immunotherapy for autoimmune diseases at the Feinberg School. The clinical trial was performed at Northwestern Memorial Hospital where Burt holds the same title. The patients in the small phase I/II trial continued to improve for up to 24 months after the transplantation procedure and then stabilized. They experienced improvements in areas in which they had been affected by multiple sclerosis including walking, ataxia, limb strength, vision and incontinence. The study will be published online January 30 and in the March issue of The Lancet Neurology. Multiple sclerosis (MS) is an autoimmune disease in which the immune system attacks the central nervous system. In its early stages, the disease is characterized by intermittent neurological symptoms, called relapsing-remitting MS. During this time, the person will either fully or partially recover from the symptoms experienced during the attacks. Common symptoms are visual problems, fatigue, sensory changes, weakness or paralysis of limbs, tremors, lack of coordination, poor balance, bladder or bowel changes and psychological changes. Within 10 to 15 years after onset of the disease, most patients with this relapsing-remitting MS progress to a later stage called secondary progressive multiple sclerosis. In this stage, they experience a steady worsening of irreversible neurological damage. The 21 patients in the trial, ages 20 to 53, had relapsing-remitting multiple sclerosis that had not responded to at least six months of treatment with interferon beta. The patients had had MS for an average of five years. After an average follow-up of three years after transplantation, 17 patients (81 percent) improved by at least one point on a disability scale. The disease also stabilized in all patients. In the procedure, Burt and colleagues treated patients with chemotherapy to destroy their immune system. They then injected the patients with their own immune stem cells, obtained from the patients' blood before the chemotherapy, to create a new immune system. The procedure is called autologous non-myeloablative haematopoietic stem-cell transplantation. "We focus on destroying only the immune component of the bone marrow and then regenerate the immune component, which makes the procedure much safer and less toxic than traditional chemotherapy for cancer," Burt said. After the transplantation, the patient's new lymphocytes or immune cells are self-tolerant and do not attack the immune system. "In MS the immune system is attacking your brain," Burt said. "After the procedure, it doesn't do that anymore." In previous studies, Burt had transplanted immune stem cells into late-stage MS patients. "It didn't help in the late stages, but when we treat them in the early stage, they get better and continue to get better," he said. "What we did is promising and exiting, but we need to prove it in a randomized trial," Burt noted. He has launched a randomized national trial. For more information visit: http://clinicaltrials.gov/ct2/show/NCT00273364 ......... ZenMaster

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Wednesday, 28 January 2009

Stem Cells Used to Reverse Paralysis in Animals

New study found transplantation of stem cells reverses paralysis in laboratory tests Wednesday, 28 January 2009 A new study has found that transplantation of stem cells from the lining of the spinal cord, called ependymal stem cells, reverses paralysis associated with spinal cord injuries in laboratory tests. The findings show that the population of these cells after spinal cord injury was many times greater than comparable cells from healthy animal subjects. The results open a new window on spinal cord regenerative strategies. The study is published in the journal Stem Cells. The transplanted cells were found to proliferate after spinal cord injury and were recruited by the specific injured area. When these cells were transplanted into animals with spinal cord injury, they regenerated ten times faster while in the transplant subject than similar cells derived from healthy control animals. Spinal cord injury is a major cause of paralysis, and the associated trauma destroys numerous cell types, including the neurons that carry messages between the brain and the rest of the body. In many spinal injuries, the cord is not actually severed, and at least some of the signal-carrying nerve cells remain intact. However, the surviving nerve cells may no longer carry messages because oligodendrocytes, which comprise the insulating sheath of the spinal cord, are lost. The regenerative mechanism discovered was activated when a lesion formed in the injured area. After a lesion formed in the transplant subject, the stem cells were found to have a more effective ability to differentiate into oligodendrocytes and other cell types needed to restore neuronal function. Currently, there are no effective therapies to reverse this disabling condition in humans. However, the presence of these stem cells in the adult human spinal cords suggests that stem cell-associated mechanisms might be exploited to repair human spinal cord injuries. Given the serious social and health problems presented by diseases and accidents that destroy neuronal function, there is an ever-increasing interest in determining whether adult stem cells might be utilized as a basis of regenerative therapies. "The human body contains the tools to repair damaged spinal cords. Our work clearly demonstrates that we need both adult and embryonic stem cells to understand our body and apply this knowledge in regenerative medicine," says Miodrag Stojkovic, Ph.D., Deputy Director and Head of the Cellular Reprogramming Laboratory at Centro de Investigacion Principe Felipe, and co-author of the study. "There are mechanisms in our body which need to be studied in more detail since they could be mobilized to cure spinal cord injuries." ......... ZenMaster

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Tuesday, 27 January 2009

Human iPS Cells Reprogrammed into Germ Cell Precursors

Discovery may lead to new treatments for infertility Tuesday, 27 January 2009 For the first time, UCLA researchers have reprogrammed human induced pluripotent stem (iPS) cells into the cells that eventually become eggs and sperm, possibly opening the door for new treatments for infertility using patient-specific cells. The iPS cells were coaxed into forming germ line precursor cells which include genetic material that may be passed on to a child. The study appears today in the early online edition of the peer-reviewed journal Stem Cells. "This finding could be important for people who are rendered infertile through disease or injury. We may, one day, be able to replace the germ cells that are lost," said Amander Clark, a Broad Stem Cell Research Center scientist and senior author of the study. "And these germ cells would be specific and genetically related to that patient." Theoretically, an infertile patient's skin cells, for example, could be taken and reprogrammed into iPS cells, which, like embryonic stem cells, have the ability to become every cell type in the human body. Those cells could then be transformed into germ line precursor cells that would eventually become eggs and sperm. Clark cautioned, however, that scientists are still many years from using these cells in patients to treat infertility. There is still much to be learned about the process of making high quality germ cells in the lab. In another important finding, Clark's team discovered that the germ line cells generated from human iPS cells were not the same as the germ line cells derived from human embryonic stem cells. Certain vital regulatory processes were not performed correctly in the human iPS derived germ cells, said Clark, an assistant professor of molecular, cell and developmental biology. So it's crucial, Clark contends, that work continue on the more controversial human embryonic stem cells that come from donated, excess material from in vitro fertilization that would otherwise be destroyed. When germ cells are formed, they need to undergo a specific series of biological processes, an essential one being the regulation of imprinted genes. This is required for the germ cells to function correctly. If these processes are not performed the resulting eggs or sperm, are at high risk for not working as they should. This has significant consequences, given that the desired outcome is a healthy child. "Further research is needed to determine if germ line cells derived from iPS cells, particularly those which have not been created by retroviral integration, have the ability to correctly regulate themselves like the cells derived from human embryonic stem cells do," Clark said. "When we looked at the germ cells derived from embryonic stem cells, we found that they regulated as expected, whereas those from the iPS cells were not regulated in the same way. We need to do much more work on this to find out why." Clark and her team plan to examine more iPS cell lines and evaluate the resulting germ cells derived from them to determine if the incorrect regulation remains a problem. Creating germ cells from embryonic stem cells is challenging and the resulting proportions are low – about 10 percent of embryonic stem cells go on to become germ cells. Clark said creating germ cells from iPS cells proved just as challenging. Putting the iPS cells in an environment where germ cells thrive naturally, among foetal gonadal cells, proved to be the key. Infertility affects about 15 percent of Americans. Current treatments include donor eggs and sperm and surrogacy. If germ cells can be derived from a patients own adult cells using reprogramming followed by germ cell differentiation, this adds an important strategy into the tool box of options currently available to treat infertility, Clark said. A man with a low sperm count, for example, may be able to have more of his own sperm generated to fertilize his partner's egg. The study took about 2 ½ years, first focusing on growing germ cells from human embryonic stem cells and then from iPS cells. It took just seven days to get germ line precursor cells from the iPS cells, once Clark and her team landed on the appropriate culture environment. ......... ZenMaster

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Scientists See Progress in FDA Stem Cell Trial Approval

ISSCR Cautions Clinical Research Still at an Early Stage Tuesday, 27 January 2009 The International Society for Stem Cell Research (ISSCR) shares in the excitement generated by the US Food and Drug Administration‘s landmark decision to approve the first clinical trials using the products of human embryonic stem cells, yet advises the public to maintain realistic expectations at this early stage. A milestone for the clinical application of stem cell research, the FDA sanctioned Geron Corporation to begin trials on patients with acute spinal cord injury. The ISSCR reiterates that the Phase I trial will focus on assessing the safety of using these cells in patients, a first step of many in determining whether this treatment can provide therapeutic benefit. Regardless of outcome, the knowledge gained from the trial will provide valuable insight for future studies as researchers continue moving stem cell research into the clinic. “The go-ahead to test products of embryonic stem cells in patients is an important first step, but only the first step on a very long journey,” said George Q. Daley, immediate past-president of the ISSCR and associate director of the Stem Cell Program at Children’s Hospital Boston. “We have so much more to learn about stem cells, and this first trial is only the beginning. We applaud Geron’s hard work and diligence getting to this point.” The approval comes after an extensive review process, which echoes the responsible, regulated and external evaluation procedures called for in the ISSCR Guidelines for the Clinical Translation of Stem Cells, released last month. “This is a great time for stem cell science,” said David Scadden, co-chair of the ISSCR Clinical Translation Committee, director of the Massachusetts General Hospital Center for Regenerative Medicine, and co-director of the Harvard Stem Cell Institute. “The FDA has signalled that the safeguards are now in place to begin testing embryonic stem cell therapies. If the White House follows through with lifting restrictions on federal funding, we could see a great flowering of new research and an opportunity to see if these cells can deliver for patients.” About ISSCR: The International Society for Stem Cell Research (ISSCR) is an independent, non-profit membership organization established to promote and foster the exchange and dissemination of information and ideas relating to stem cells, to encourage the general field of research involving stem cells and to promote professional and public education in all areas of stem cell research and application. ......... ZenMaster

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Friday, 23 January 2009

Geron Get FDA Clearance for First Test of Human Embryonic Stem Cell Therapy

Geron to Study GRNOPC1 in Patients with Acute Spinal Cord Injury Friday, 23 January 2009 Geron Corporation announced today that the US Food and Drug Administration (FDA) has granted clearance of the company's Investigational New Drug (IND) application for the clinical trial of GRNOPC1 in patients with acute spinal cord injury. The clearance enables Geron to move forward with the world's first study of a human embryonic stem cell (hESC)-based therapy in man. Geron plans to initiate a Phase I multi-centre trial that is designed to establish the safety of GRNOPC1 in patients with "complete" American Spinal Injury Association (ASIA) grade A subacute thoracic spinal cord injuries. "The FDA's clearance of our GRNOPC1 IND is one of Geron's most significant accomplishments to date," said Thomas Okarma, Ph.D., M.D., Geron's president and CEO. "This marks the beginning of what is potentially a new chapter in medical therapeutics – one that reaches beyond pills to a new level of healing: the restoration of organ and tissue function achieved by the injection of healthy replacement cells. The ultimate goal for the use of GRNOPC1 is to achieve restoration of spinal cord function by the injection of hESC-derived oligodendrocyte progenitor cells directly into the lesion site of the patient's injured spinal cord." GRNOPC1, Geron's lead hESC-based therapeutic candidate, contains hESC-derived oligodendrocyte progenitor cells that have demonstrated remyelinating and nerve growth-stimulating properties leading to restoration of function in animal models of acute spinal cord injury (Journal of Neuroscience, Vol. 25, 2005). "The neurosurgical community is very excited by this new approach to treating devastating spinal cord injury," said Richard Fessler, M.D., Ph.D., professor of neurological surgery at the Feinberg School of Medicine at Northwestern University. "Demyelination is central to the pathology of the injury, and its reversal by means of injecting oligodendrocyte progenitor cells would be revolutionary for the field. If safe and effective, the therapy would provide a viable treatment option for thousands of patients who suffer severe spinal cord injuries each year." The GRNOPC1 Clinical Program Patients eligible for the Phase I trial must have documented evidence of functionally complete spinal cord injury with a neurological level of T3 to T10 spinal segments and agree to have GRNOPC1 injected into the lesion sites between seven and 14 days after injury. Geron has selected up to seven US medical centres as candidates to participate in this study and in planned protocol extensions. The sites will be identified as they come online and are ready to enrol subjects into the study. Although the primary endpoint of the trial is safety, the protocol includes secondary endpoints to assess efficacy, such as improved neuromuscular control or sensation in the trunk or lower extremities. Once safety in this patient population has been established and the FDA reviews clinical data in conjunction with additional data from ongoing animal studies, Geron plans to seek FDA approval to extend the study to increase the dose of GRNOPC1, enrol subjects with complete cervical injuries and expand the trial to include patients with severe incomplete (ASIA grade B or C) injuries to enable access to the therapy for as broad a population of severe spinal cord-injured patients as is medically appropriate. Preclinical Evidence of Safety, Tolerability and Efficacy Geron submitted evidence of the safety, tolerability and efficacy of GRNOPC1 to the FDA in a 21,000-page IND application that described 24 separate animal studies requiring the production of more than five billion GRNOPC1 cells. Included in the safety package were studies that showed no evidence of teratoma formation 12 months after injection of clinical grade GRNOPC1 into the injured spinal cord of rats and mice. Other studies documented the absence of significant migration of the injected cells outside the spinal cord, allodynia induction (increased neuropathic pain due to the injected cells), systemic toxicity or increased mortality in animals receiving GRNOPC1. In vitro studies have shown that GRNOPC1 is minimally recognized by the human immune system. GRNOPC1 is not recognized in vitro by allogeneic sera, NK cells or T cells (Journal of Neuroimmunology, Vol. 192, 2007). These immune-privileged characteristics of the hESC-derived cells allow a clinical trial design that incorporates a limited course of low-dose immunosuppression and provide the rationale for an off-the-shelf, allogeneic cell therapy. Also included in the IND application were published studies supporting the utility of GRNOPC1 for the treatment of spinal cord injury. Those studies showed that administration of GRNOPC1 significantly improved locomotor activity and kinematic scores of animals with spinal cord injuries when injected seven days after the injury (Journal of Neuroscience, Vol. 25, 2005). Histological examination of the injured spinal cords treated with GRNOPC1 showed improved axon survival and extensive remyelination surrounding the rat axons. These effects of GRNOPC1 were present nine months after a single injection of cells. In these nine-month studies, the cells were shown to migrate and fill the lesion cavity, with bundles of myelinated axons crossing the injury site. Production and Qualification of GRNOPC1 GRNOPC1 is produced using current Good Manufacturing Practices (cGMP) in Geron's manufacturing facilities. Geron's GRNOPC1 production process and clean-room suites have been inspected and licensed by the state of California. The cells are derived from the H1 human embryonic stem cell line, which was created before August 9, 2001. Studies using this line qualify for US federal research funding, although no federal funding was received for the development of the product or to support the clinical trial. Geron's H1 hESC master cell bank is fully qualified for human use and was shown to be karyotypically normal and free of measurable contaminants of human or animal origin. Production of GRNOPC1 from undifferentiated hESCs in the master cell bank uses qualified reagents and a standardized protocol developed at Geron over the past three years. Each manufacturing run of GRNOPC1 is subjected to standardized quality control testing to ensure viability, sterility and appropriate cellular composition before release for clinical use. GRNOPC1 product that has passed all such specifications and has been released, is available for the approved clinical trial. The current production scale can supply product needs through pivotal clinical trials. The existing master cell bank could potentially supply sufficient starting material for GRNOPC1 to commercially supply the US acute spinal cord injury market for more than 20 years. Intellectual Property A portfolio of patent rights owned by or exclusively licensed to Geron protects the production and commercialization of GRNOPC1. Patent rights owned by Geron protect key technologies developed at Geron for the scalable manufacturing of hESCs, as well as the production of neural cells by differentiation of hESCs. The fundamental patents covering hESCs are exclusively licensed to Geron from the Wisconsin Alumni Research Foundation (WARF) for the production of neural cells, cardiomyocytes and pancreatic islets for therapeutic applications. The validity of these patents was recently confirmed by the US Patent and Trademark Office in a re-examination proceeding. Geron funded the original research at the University of Wisconsin-Madison that led to the first isolation of hESCs. Patent rights exclusively licensed to Geron from the University of California cover the production of oligodendrocytes from hESCs. These patent rights cover technology developed in a research collaboration between Geron and University of California scientists. About Geron Geron is developing first-in-class biopharmaceuticals for the treatment of cancer and chronic degenerative diseases, including spinal cord injury, heart failure and diabetes. The company is advancing an anti-cancer drug and a cancer vaccine that target the enzyme telomerase through multiple clinical trials. Geron is also the world leader in the development of human embryonic stem (hESC) cell-based therapeutics. The company has received FDA clearance to begin the world's first human clinical trial of a hESC-based therapy: GRNOPC1 for acute spinal cord injury. ......... ZenMaster

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Monday, 19 January 2009

Parasites in the Genome

A molecular parasite could play an important role in human evolution Monday, 19 January 2009 Researchers at the Max Planck Institute for Developmental Biology in Tübingen, Germany, determined the structure of a protein (L1ORF1p), which is encoded by a parasitic genetic element and which is responsible for its mobility. The so-called LINE-1 retrotransposon is a mobile genetic element that can multiply and insert itself into chromosomal DNA at many different locations. This disturbs the genetic code at the site of integration, which can have serious consequences for the organism. On the other hand, this leads to genetic variation, an absolute prerequisite for the evolution of species. The structure of the L1ORF1p protein now allows a much more precise investigation of the mechanism of LINE-1 mobilization. This provides new insight into the relation between retrotransposons and retroviruses and probably also into certain evolutionary processes in humans and animals. Moreover, the researchers assume that the mechanism of LINE-1 retrotransposition can be exploited one day to precisely insert genetic information into specific locations. This would be an alternative to contemporary, less location-specific methods that are based on a retroviral mechanism. (PNAS, January 20th, 2009) The LINE-1 retrotransposon is a mobile gene that has multiplied massively in the history of the human genome. Presently, approximately 17 per cent of our DNA consists of LINE-1 sequences. This is an enormous proportion if one considers that the roughly 30.000 human proteins are encoded by less that 5 per cent of the DNA. The LINE-1 retrotransposon not only propagates itself, but also is responsible for the genomic integration of approximately one million Alu-sequences (another parasitic gene). Alu-sequences are only present in higher primates and occupy another 10 per cent of our genome. The insertion of LINE-1 and Alu-sequences is a continuous process and roughly every twentieth newborn is estimated to contain at least one new insertion of such an element. Consequently, there rarely is a human gene that has not been affected in the past by the integration of a LINE-1 or Alu element.

Retrotransposition cycle of the human LINE-1 element. LINE-1-RNA is transcribed in the nucleus from genomic DNA. Subsequently, in the cytosol, it gets translated into two proteins (L1ORF1p and L1ORF2p) by the ribosome. Both proteins then bind LINE-1 RNA and form an RNA-protein complex. Back in the nucleus the L1ORF2p protein nicks chromosomal DNA and begins with the reverse transcription of LINE-1 RNA into DNA, which gets integrated into the genome at the place of the nick. L1ORF1p likely supports this process. Credit: Elena Khazina and Oliver Weichenrieder, Max Planck Institute for Developmental Biology.

“It is difficult to believe that the massive integration of LINE-1 and Alu sequences remained without consequences on human evolution. Thus it is surprising how little we know so far about the mechanism of retrotransposition and about the proteins and nucleic acids involved in this process“, says Oliver Weichenrieder, leading scientists at the Max Planck Institute for Developmental Biology. The researchers therefore try to gain new insights via the biochemical characterisation of the involved molecules and via the determination of their molecular structures. This provides the basis for a detailed functional analysis and reveals similarities to already known proteins, especially similarities that are not obvious from a simple comparison of the respective amino acid sequences. In the present work Elena Khazina und Oliver Weichenrieder characterize one of two proteins that are encoded by the human LINE-1 retrotransposon. This so-called L1ORF1p protein binds to LINE-1 RNA, which was transcribed from a LINE-1 element in the genomic DNA. Subsequently, L1ORF1p likely supports the following reverse transcription of LINE-1 RNA into DNA. This process happens directly at the genomic integration site of the new LINE-1 element. The researchers show that the L1ORF1p protein consists of three parts. The first part causes a self-association such that always three molecules come together to form a trimer. The other two parts are necessary for binding LINE-1 RNA. “Especially surprising was the identification of a so-called RRM domain in the middle part of the protein, since this part was believed so far to be rather unstructured”, says Elena Khazina. “Our crystal structure clearly proves the existence of this domain. Meanwhile we identified RRM-domains also in other retrotransposons, in a variety of animal and plant species“, adds the structural biologist.

A. Scheme of the L1ORF1p trimer. B. Crystal structure of the RRM-domain of the human L1ORF1p protein. Credit: Elena Khazina and Oliver Weichenrieder, Max Planck Institute for Developmental Biology.

RRM-domains (RNA Recognition Motif) occur frequently in the cell, particularly in RNA-binding proteins. The existence of an RRM-domain in L1ORF1p now explains why L1ORF1p binds LINE-1 RNA and how this could happen in detail. The insight into the structure of the L1ORF1p protein provides a new perspective and a good basis for future investigations of those cellular processes that are exploited by the LINE-1 element for its own propagation, and also for those mechanisms that are available to the cell to prevent the excessive propagation of retrotransposons. Reference: Non-LTR retrotransposons encode noncanonical RRM domains in their first open-reading frame. Elena Khazina, Oliver Weichenrieder PNAS, 12 January 2009, vol. 106 (3), 731-736, doi: 10.1073/pnas0809964106 ......... ZenMaster

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Large DNA Stretches, Not Single Genes, Shut Off as Stem Cells Mature

Epigenetic finding adds insight on how cells become brain, liver – and malignant cells Monday, 19 January 2009 Experiments at Johns Hopkins Medical Institutions have found that the gradual maturing of embryonic cells into cells as varied as brain, liver and immune system cells is apparently due to the shut off of several genes at once rather than in individual smatterings as previous studies have implied. Working with mouse brain and liver cells, as well as embryonic stem cells, Johns Hopkins University School of Medicine professor Andrew Feinberg, M.D., M.P.H., led an investigation of a kind of epigenetic modification to histones, the molecular "spools" that DNA winds around in the cell nucleus. This modification is a variety of the so-called epigenetic changes that alter the function of cells without directly altering the nuclear DNA in the cells. Other scientists had previously found that histone modifications appear to silence individual genes in the DNA that coils around affected histones. But when Feinberg and his team compared the activity of thousands of genes in the liver and brain cells, they found that a particular modification — in which two methyl groups clip onto histones — seemed to silence long stretches of DNA containing many genes at once. The findings will publish in Nature Genetics online on Jan. 18. Since the silenced stretches varied greatly between the different types of cells, Feinberg, postdoctoral fellow Bo Wen, and their colleagues wondered whether these sections — called large organized chromatin K9 modifications, or LOCKS — might be responsible for the transition from the "blank slate" quality of embryonic cells to the specialized functions that mature cells take on. To find out, he and his team looked for LOCKs in mouse embryonic stem cells. Unlike mature, adult liver and brain cells, in which about 40 percent of the genome was silenced by LOCKs, the embryonic stem cells had no LOCKs. Next, the researchers compared the regions of DNA affected by LOCKs between mouse liver and brain cells and their corresponding human cells. The same cell types in both organisms had remarkably similar regions of DNA silenced by LOCKs, suggesting that the same genes necessary to control cell function are affected in mice and people. "These results suggest that LOCKs appear gradually during development, refining cells' functions as they differentiate into particular cell types," Wen says. "Our experiments suggest that the whole forest of genes is changing, but people have been looking at the individual trees." Because epigenetic changes also are known to play a role in abnormal cell growth, the researchers suspected that LOCKs were involved in the development of cancer. When they looked for genes in several common cancer cell lines often used in research, they indeed found significantly fewer LOCKs than in normal liver and brain cells. "In cancer, some of these LOCKs may become unlocked," says Feinberg. "Sections of DNA that were silenced in a cell type might become active, giving cancer cells characteristics of other cell types that they're not supposed to have." Feinberg says this "unlocking" might cause cancer cells to revert to a more immature developmental state, explaining some of their unusual behaviour, such as extreme proliferation or migration to different areas of the body. Reference: The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores Rafael A Irizarry, Christine Ladd-Acosta, Bo Wen, Zhijin Wu, Carolina Montano, Patrick Onyango, Hengmi Cui, Kevin Gabo, Michael Rongione, Maree Webster, Hong Ji, James B Potash, Sarven Sabunciyan & Andrew P Feinberg Nature Genetics, 18 January 2009, doi:10.1038/ng.298 ......... ZenMaster

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Friday, 16 January 2009

Discovery of Methane Reveals Mars Is Not a Dead Planet

Discovery of Methane Reveals Mars Is Not a Dead Planet Friday, 16 January 2009 A team of NASA and university scientists has achieved the first definitive detection of methane in the atmosphere of Mars. This discovery indicates the planet is either biologically or geologically active. The team found methane in the Martian atmosphere by carefully observing the planet throughout several Mars years with NASA's Infrared Telescope Facility and the W.M. Keck telescope, both at Mauna Kea, Hawaii. The team used spectrometers on the telescopes to spread the light into its component colours, as a prism separates white light into a rainbow. The team detected three spectral features called absorption lines that together are a definitive signature of methane. "Methane is quickly destroyed in the Martian atmosphere in a variety of ways, so our discovery of substantial plumes of methane in the northern hemisphere of Mars in 2003 indicates some ongoing process is releasing the gas," said Michael Mumma of NASA's Goddard Space Flight Center in Greenbelt, Md.

Methane Plume on Mars

This image shows concentrations of Methane discovered on Mars. The first definitive detection of methane in the atmosphere of Mars indicates the planet is alive in the sense that it still has geologic activity powered by heat from its interior, according to a team of NASA and university scientists. The team used spectrometer instruments attached to several telescopes to detect plumes of methane that were emitted from specific sites during the warmer seasons – spring and summer. Though nothing conclusive can yet be determined, it is possible that the detected methane was either produced by geologic processes such as the oxidation of iron (serpentinization) or by microscopic Martian life below the planet’s surface. The methane released today could be produced currently, or it could be ancient methane trapped in ice 'cages' called clathrates or as gas below a sub-surface ice layer. Credit: NASA/Goddard Space Flight Center Scientific Visualization Studio.

"At northern mid-summer, methane is released at a rate comparable to that of the massive hydrocarbon seep at Coal Oil Point in Santa Barbara, Calif." Mumma is lead author of a paper describing this research that will appear in Science Express on Thursday. Methane, four atoms of hydrogen bound to a carbon atom, is the main component of natural gas on Earth. Astrobiologists are interested in these data because organisms release much of Earth's methane as they digest nutrients. However, other purely geological processes, like oxidation of iron, also release methane. "Right now, we do not have enough information to tell whether biology or geology — or both — is producing the methane on Mars," Mumma said. "But it does tell us the planet is still alive, at least in a geologic sense. It is as if Mars is challenging us, saying, 'hey, find out what this means.' " If microscopic Martian life is producing the methane, it likely resides far below the surface where it is warm enough for liquid water to exist. Liquid water is necessary for all known forms of life, as are energy sources and a supply of carbon. "On Earth, microorganisms thrive about 1.2 to 1.9 miles beneath the Witwatersrand basin of South Africa, where natural radioactivity splits water molecules into molecular hydrogen and oxygen," Mumma said. "The organisms use the hydrogen for energy. It might be possible for similar organisms to survive for billions of years below the permafrost layer on Mars, where water is liquid, radiation supplies energy, and carbon dioxide provides carbon. Gases, like methane, accumulated in such underground zones might be released into the atmosphere if pores or fissures open during the warm seasons, connecting the deep zones to the atmosphere at crater walls or canyons." It is possible a geologic process produced the Martian methane, either now or eons ago. On Earth, the conversion of iron oxide into the serpentine group of minerals creates methane, and on Mars this process could proceed using water, carbon dioxide and the planet's internal heat. Although there is no evidence of active volcanism on Mars today, ancient methane trapped in ice cages called clathrates might be released now. "We observed and mapped multiple plumes of methane on Mars, one of which released about 19,000 metric tons of methane," said co-author Geronimo Villanueva of the Catholic University of America in Washington. "The plumes were emitted during the warmer seasons, spring and summer, perhaps because ice blocking cracks and fissures vaporized, allowing methane to seep into the Martian air."

Plumes appeared over the Martian northern hemisphere regions such as east of Arabia Terra, the Nili Fossae region, and the south-east quadrant of Syrtis Major, an ancient volcano about 745 miles across. Credit: NASA/Goddard Space Flight Center Scientific Visualization Studio.

According to the team, the plumes were seen over areas that show evidence of ancient ground ice or flowing water. Plumes appeared over the Martian northern hemisphere regions such as east of Arabia Terra, the Nili Fossae region, and the south-east quadrant of Syrtis Major, an ancient volcano about 745 miles across. One method to test whether life produced this methane is by measuring isotope ratios. Isotopes of an element have slightly different chemical properties, and life prefers to use the lighter isotopes. A chemical called deuterium is a heavier version of hydrogen. Methane and water released on Mars should show distinctive ratios for isotopes of hydrogen and carbon if life was responsible for methane production. It will take future missions, like NASA's Mars Science Laboratory, to discover the origin of the Martian methane. References: Strong Release of Methane on Mars in Northern Summer 2003 Michael J. Mumma, Geronimo L. Villaneuva, Robert E. Novak, Tilak Hewagama, Boncho P. Bonev, Michael A. DiSanti, Avi M. Mandell, and Michael D. Smith Science, Published Online January 15, 2009, DOI: 10.1126/science.1165243 Martian Methane Reveals the Red Planet is not a Dead Planet Bill Steigerwald NASA - 15 January 2009 ......... ZenMaster

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Thursday, 15 January 2009

Bone Marrow Stem Cells Regenerate Skin

New study suggests that adult bone marrow stem cells can be used in the construction of artificial skin Thursday, 15 January 2009 A new study suggests that adult bone marrow stem cells can be used in the construction of artificial skin. The findings mark an advancement in wound healing and may be used to pioneer a method of organ reconstruction. The study is published in Artificial Organs, official journal of the International Federation for Artificial Organs (IFAO), the The International Faculty for Artificial Organs (INFA) and the International Society for Rotary Blood Pumps (ISRBP). To investigate the practicability of repairing burn wounds with tissue-engineered skin combined with bone marrow stem cells, the study established a burn wound model in the skin of pigs, which is known to be anatomically and physiologically similar to human skin. Engineering technology and biomedical theory methods were used to make artificial skin with natural materials and bone marrow derived stem cells. Once the artificial skin was attached to the patient and the dermal layer had begun to regenerate, stem cells were differentiated into skin cells. The cells are self-renewing and raise the quality of healing in wound healing therapy. When grafted to the burn wounds, the engineered skin containing stem cells showed better healing, less wound contraction and better development of blood vessels. Skin, the human body's largest organ, protects the body from disease and physical damage, and helps to regulate body temperature. When the skin has been seriously damaged through disease or burns, the body often cannot act fast enough to repair them. Burn victims may die from infection and the loss of plasma. Skin grafts were originally developed as a way to prevent such consequences. "We hope that this so-called 'engineered structural tissue' will someday replace plastic and metal prostheses currently used to replace damaged joints and bones by suitable materials and stem cells," says Yan Jin of the Fourth Military Medical University, lead author of the study. Yan Jin is a chair professor and director of the Department of Oral Histology and Pathology of the School of Stomatology, and director of the Center of Tissue Engineering at the Fourth Military Medical University, Xian, China. ......... ZenMaster

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Saturday, 10 January 2009

GM Goats Make Anti-clotting Drug in Their Milk

FDA approval is pending Saturday, 10 January 2009 An anti-clotting drug made from the milk of genetically engineered goats moved closer to government approval Wednesday after experts at the Food and Drug Administration reported that the medication works and its safety is acceptable. Company data showed the drug was safe and effective, a majority of the Food and Drug Administration's 19-member panel voted. The FDA will consider the advice in making its decision, expected by February 7. Called ATryn, the drug is intended to help people with a rare hereditary disorder that makes them vulnerable to life-threatening blood clots.

A Massachusetts biotechnology company, GTC Biotherapeutics, developed ATryn by altering the genes of goats so they would produce milk rich in human antithrombin, a protein that in humans acts as a natural blood thinner. Scientists at the GTC have made the drug by inserting the human antithrombin protein into single cell embryos of goats. These embryos were then put into the wombs of surrogate mothers who produced goats that possessed the new characteristics. The protein is gathered from the milk of the goat, which is then refined and purified. The scientific advisors at the FDA will see into the pros and cons of ATryn. They will then make a further recommendation for approval of the drug. “It's the first time we've held an advisory committee meeting on any product from a genetically engineered animal,” FDA spokeswoman Siobhan DeLancey said. If the drug is approved, then this would be a significant leap in the area of making medicines by altering genes of living organisms. GTC Biotherapeutics says that a single goat will produce more than six pounds of the protein in the course of a year, and also notes that the drug-producing trait will be naturally passed down to the next generation of goats. The company has a herd of about 200 at its Massachusetts facility, which are otherwise normal and screened for viruses, GTC said. “The real dramatic thing that is happening here is that we've been able to reduce some very clever science to the practical level of producing a drug that's safe and efficacious,” said Geoffrey Cox, Chairman GTC. The drug is licensed to Ovation Pharmaceuticals Inc in the United States. ......... ZenMaster

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Friday, 9 January 2009

Growth of New Brain Cells Requires ‘Epigenetic’ Switch

Growth of New Brain Cells Requires ‘Epigenetic’ Switch Friday, 09 January 2009 New cells are born every day in the brain's hippocampus, but what controls this birth has remained a mystery. Reporting in the January 1 issue of Science, neuroscientists at the Johns Hopkins University School of Medicine have discovered that the birth of new cells, which depends on brain activity, also depends on a protein that is involved in changing epigenetic marks in the cell's genetic material. "How is it that when you see someone you met ten years ago, you still recognize them? How do these transient events become long lasting in the brain, and what potential role does the birth of new neurons play in making these memories?" says Hongjun Song, Ph.D., an associate professor of neurology and member of the Johns Hopkins Institute of Cell Engineering's NeuroICE. "We really want to understand how daily life experiences trigger the birth and growth of new neurons, and make long-lasting changes in the brain." The researchers reasoned that making long-term memories might require long-term changes in brain cells. And one type of cellular change that has long-lasting effects is so-called epigenetic change, which can alter a cell's DNA without changing its sequence but does change how and which genes are turned on or off. So they decided to look at the 40 to 50 genes known to be involved in epigenetics, and see if any of them are turned on in mouse brain cells that have been stimulated with electroconvulsive therapy (ECT) — shock treatment. "It's long been known that ECT induces neurogenesis in rodents and humans, so we used it as our test case to find what is triggered downstream to cause new cells to grow," says Song. One gene turned on in response to ECT was Gadd45b, a gene previously implicated in immune system function and misregulated in brain conditions like autism. To confirm Gadd45b is turned up in response to brain activity, the researchers also examined mice experiencing a different activity. Exposure to new surroundings, the team found, also turns on Gadd45b in brain cells. To find out if Gadd45b is required for new brain-cell growth, the research team made mice lacking the Gadd45b gene and tested their ability to generate new brain cells after ECT. They injected the mice with a dye that marks new cells and three days after ECT examined the number of new cells containing that dye in brains from mice with and without the Gdd45b gene. They found that while normal brains showed a 140 percent increase in cell number after ECT, brains lacking Gadd45b only showed a 40 percent increase. "The question then was, How does Gadd45b do this?" says Song. "It's been controversial that Gadd45b can promote epigenetic changes like global DNA demethylation, but we show that it can promote demethylation of certain genes." The chemical methyl group, when attached to DNA near genes, can turn those genes off. This so-called epigenetic change is thought to silence genes a cell does not use. By dissecting mature neurons from normal mouse brains and looking for the presence of methyl groups at certain genes known to promote cell growth, the researchers found that after ECT, these genes became demethylated. However, doing the same thing with mice lacking Gadd45b resulted in no demethylation, suggesting to the team that Gadd45b is indeed required for demethylation. "We're really excited about this — it's the first time we've seen dynamic epigenetic DNA changes in response to brain activity," says Song. "Now that we have the mice lacking Gadd45b, our next goal is to see if these mice have problems with learning and memory and how Gadd45b specifically promotes the demethylation to lead to these long-term changes in the brain." Reference: Neuronal Activity–Induced Gadd45b Promotes Epigenetic DNA Demethylation and Adult Neurogenesis Dengke K. Ma, Mi-Hyeon Jang, Junjie U. Guo, Yasuji Kitabatake, Min-lin Chang, Nattapol Pow-anpongkul, Richard A. Flavell, Binfeng Lu, Guo-li Ming, and Hongjun Song Science, January 1 2009; 10.1126/science.1166859 ......... ZenMaster

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Thursday, 8 January 2009

Extra Stem Cells to Repair the Body

Use of new drug combinations to stimulate bone marrow stem cell release Thursday, 08 January 2009 Scientists have tricked bone marrow into releasing extra adult stem cells into the bloodstream, a technique that they hope could one day be used to repair heart damage or mend a broken bone, in a new study published today in the journal Cell Stem Cell. When a person has a disease or an injury, the bone marrow mobilises different types of stem cells to help repair and regenerate tissue. The new research, by researchers from Imperial College London, shows that it may be possible to boost the body's ability to repair itself and speed up repair, by using different new drug combinations to put the bone marrow into a state of 'red alert' and send specific kinds of stem cells into action. In the new study, researchers tricked the bone marrow of healthy mice into releasing two types of adult stem cells – mesenchymal stem cells, which can turn into bone and cartilage and that can also suppress the immune system, and endothelial progenitor cells, which can make blood vessels and therefore have the potential to repair damage in the heart. This study, funded by the British Heart Foundation and the Wellcome Trust, is the first to selectively mobilise mesenchymal stem cells and endothelial progenitor cells from the bone marrow. Previous studies have only been able to mobilise the haematopoietic type of stem cell, which creates new blood cells. This technique is already used in bone marrow transplants in order to boost the numbers of haematopoietic stem cells in a donor's bloodstream. The researchers were able to choose which groups of stem cells the bone marrow released, by using two different therapies. Ultimately, the researchers hope that their new technique could be used to repair and regenerate tissue, for example, when a person has heart disease or a sports injury, by mobilising the necessary stem cells. The researchers also hope that they could tackle autoimmune diseases such as rheumatoid arthritis, where the body is attacked by its own immune system, by kicking the mesenchymal stem cells into action. These stem cells are able to suppress the immune system. Dr Sara Rankin, the corresponding author of the study from the National Heart & Lung Institute at Imperial College London, said: "The body repairs itself all the time. We know that the skin heals over when we cut ourselves and, similarly, inside the body there are stem cells patrolling around and carrying out repair where it's needed. However, when the damage is severe, there are limits to what the body can do of its own accord.” "We hope that by releasing extra stem cells, as we were able to do in mice in our new study, we could potentially call up extra numbers of whichever stem cells the body needs, in order to boost its ability to mend itself and accelerate the repair process. Further down the line, our work could lead to new treatments to fight various diseases and injuries which work by mobilising a person's own stem cells from within," added Dr Rankin. The scientists reached their conclusions after treating healthy mice with one of two different 'growth factors' – proteins that occur naturally in the bone marrow – called VEGF and G-CSF. Following this treatment, the mice were given a new drug called Mozobil. The researchers found that the bone marrow released around 100 times as many endothelial and mesenchymal stem cells into the bloodstream when the mice were treated with VEGF and Mozobil, compared with mice that received no treatment. Treating the mice with G-CSF and Mozobil mobilised the haematopoietic stem cells – this treatment is already used in bone marrow transplantation. The researchers now want to investigate whether releasing repair stem cells into the blood really does accelerate the rate and degree of tissue regeneration in mice that have had a heart attack. Depending on the outcome of this work, they hope to conduct clinical trials of the new drug combinations in humans within the next ten years. The researchers are also keen to explore whether ageing or having a disease affects the bone marrow's ability to produce different kinds of adult stem cells. They want to investigate if the new technique might help to reinvigorate the body's repair mechanisms in older people, to help them fight disease and injury. Reference: Differential Mobilization of Subsets of Progenitor Cells from the Bone Marrow Simon C. Pitchford, Rebecca C. Furze, Carla P. Jones, Antje M. Wengner, Sara M. Rankin Cell Stem Cell, Volume 4, Issue 1, 62-72, 9 January 2009, doi:10.1016/j.stem.2008.10.017 ......... ZenMaster

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Making Perfect Protein: Lost in Translation

Perfectionist protein-maker trashes errors Thursday, 08 January 2009

The enzyme machine that translates a cell's DNA code into the proteins of life is nothing if not an editorial perfectionist. Johns Hopkins researchers, reporting this week in Nature, have discovered a new "proofreading step" during which the suite of translational tools called the ribosome recognizes errors, just after making them, and definitively responds by hitting its version of a "delete" button. It turns out, the Johns Hopkins researchers say, that the ribosome exerts far tighter quality control than anyone ever suspected over its precious protein products which, as workhorses of the cell, carry out the very business of life. "What we now know is that in the event of miscoding, the ribosome cuts the bond and aborts the protein-in-progress, end of story," says Rachel Green, a Howard Hughes Medical Institute investigator and professor of molecular biology and genetics in the Johns Hopkins University School of Medicine. "There's no second chance." Previously, Green says, molecular biologists thought the ribosome tightly managed its actions only prior to the actual incorporation of the next building block by being super-selective about which chemical ingredients it allows to enter the process. Because a protein's chemical "shape" dictates its function, mistakes in translating assembly codes can be toxic to cells, resulting in the misfolding of proteins often associated with neurodegenerative conditions. Working with bacterial ribosome’s, Green and her team watched them react to lab-induced chemical errors and were surprised to see that the protein-manufacturing process didn't proceed as usual, getting past the error and continuing its "walk" along the DNA's protein-encoding genetic messages. "We thought that once the mistake was made, it would have just gone on to make the next bond and the next," Green says. "But instead, we noticed that one mistake on the ribosomal assembly line begets another, and it's this compounding of errors that leads to the partially finished protein being tossed into the cellular trash," she adds. To their further surprise, the ribosome lets go of error-laden proteins 10,000 times faster than it would normally release error-free proteins, a rate of destruction that Green says is "shocking" and reveals just how much of a stickler the ribosome is about high-fidelity protein synthesis. "These are not subtle numbers," she says, noting that there is a clear biological cost for this ribosomal editing and jettisoning of errors, but a necessary expense. "The cell is a wasteful system in that it makes something and then says, forget it, throw it out," Green concedes. "But it's evidently worth the waste to increase fidelity. There are places in life where fidelity matters." ......... ZenMaster

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Converting Adult Somatic Cells to Pluripotent Stem Cells Using a Single Virus

A single lentiviral vector of the expression of a 'stem cell cassette' dramatically boosts reprogramming efficiency and puts iPS technology one step closer toward human clinical trials. Thursday, 08 January 2009 A Boston University School of Medicine-led research team has discovered a more efficient way to create induced pluripotent stem (iPS) cells, derived from mouse fibroblasts, by using a single virus vector instead of multiple viruses in the reprogramming process. The result is a powerful laboratory tool and a significant step toward the application of embryonic stem cell-like cells for clinical purposes such as the regeneration of organs damaged by inherited or degenerative diseases, including emphysema, diabetes, inflammatory bowel disease, and Alzheimer's Disease. Their research titled "iPS Cell Generation Using a Single Lentiviral Stem Cell Cassette" appears on line in the journal Stem Cells. Prior research studies have required multiple retroviral vectors for reprogramming — steps that depended on four different viruses to transfer genes into the cells' DNA – essentially a separate virus for each reprogramming gene (Oct4. Klf4, Sox2 and c-Myc). Upon activation, these genes convert the cells from their adult, differentiated status to what amounts to an embryonic-like state. However, the high number of genomic integrations — 15 to 20 — that typically occurs when multiple viruses are used for reprogramming, poses a safety risk in humans, as some of these genes (i.e. c-Myc) can cause cancer. In addition, the viruses can integrate in cell locations turning on potential oncogenes. The major milestone the six-member research team, led by Gustavo Mostoslavsky, Boston University Assistant Professor of Medicine in the Gastroenterology Section, achieved was combining the four vectors into a single "stem cell cassette" containing all four genes. The cassette (named STEMCCA) is comprised of a single multi-cistronic mRNA encoding the four transcription factors using a combination of 2A peptide technology and an internal ribosomal entry site (IRES). With the STEMCCA vector, the researchers were able to generate iPS cells more efficiently — 10 times higher than previously reported studies. "The use of a single lentiviral vector for the derivation of iPS cells will help reduce the variability in efficiency that has been observed between different laboratories, thus enabling more consistent genetic and biochemical characterizations of iPS cells and the reprogramming process," the researchers concluded. "We believe that the specific design of the cassette together with the fact that all four genes are expressed from the same transcript could account for the high efficiency we obtained" commented Cesar A. Sommer, first author in the paper and a postdoctoral fellow at Boston University Medical School's Gastroenterology Section. Most importantly, several iPS clones were generated with a single viral integration, a major advance compared to the multiple integrations observed in other studies. "Now we could move forward toward the elimination of the whole cassette using recombination technologies", noted Mostoslavsky. Darrell N. Kotton, another co-author on the paper and an Assistant Professor at Boston University Medical School's Pulmonary Section mentioned that preliminary studies already confirmed that the STEMCCA vector works with high efficiency for the reprogramming of human cells. Reference: iPS Cell Generation Using a Single Lentiviral Stem Cell Cassette Cesar A. Sommer, Matthias Stadtfeld, George J. Murphy, Konrad Hochedlinger, Darrell N. Kotton, Gustavo Mostoslavsky Stem Cells, December 18, 2008; doi:10.1634/stemcells.2008-1075 ......... ZenMaster

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Wednesday, 7 January 2009

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

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