Repair Of DNA By Brca2 Gene Prevents Medulloblastoma

Investigators at St. Jude Children's Research Hospital have gained some of the first major insights into how certain genes known to prevent cancer also guide the normal development of the nervous system before birth and during infancy by repairing DNA damage.


The St. Jude researchers demonstrated that the Brca2 gene plays a dual role in the developing nervous system, eliminating errors in the DNA of newly made copies of chromosomes and suppressing the onset of the brain cancer medulloblastoma. Medulloblastoma is a cancer of the cerebellum the lower back part of the brain that controls complex motor functions and communicates with other parts of the brain. This cancer accounts for about 20 percent of childhood brain tumors, about half of which occur in children younger than six years.


The role of Brca2 is important because as the cerebellum grows in size and complexity before and shortly after birth, it rapidly produces many new nerve cells.


"Our study showed that the Brca2 gene acts as a surveillance mechanism that triggers repair of DNA that is damaged when the cell makes a duplicate set of its chromosomes each time it divides," said Peter McKinnon, Ph.D., associate member of the Genetics and Tumor Cell Biology department at St. Jude. "The enormous rate of cell divisions during growth of the cerebellum greatly increases the risk of DNA damage. So the cell must have a way to ensure that the damage is quickly repaired to prevent the accumulation of abnormal cells that can cause abnormalities, such as medulloblastoma." McKinnon is senior author of a report on this work in the advanced online version of The EMBO Journal (doi: 10.1038/sj.emboj.7601703).


When researchers eliminated Brca2 from the developing nervous system in mice, the loss of this gene led to widespread apoptosis, or cell suicide, triggered by the cell's inability to repair DNA damage. This reduced the size of the cerebellum, led to malformation in the shape of the brain and disrupted the movement of certain nerves cells that normally migrate through the cerebellum during development. When the team blocked cell suicide by eliminating both copies of p53, a gene needed to trigger apoptosis, the brain developed its normal size, but most of the mice developed medulloblastoma.


The study also gave the St. Jude researchers insights into a childhood disease called Fanconi anemia, which is caused by a mutation in the human version Brca2. Children with Fanconi anemia are at increased risk for tumors and small brain size, among other problems. In the current study, the St. Jude team showed that mice lacking Brca2 had neurologic defects similar to those of humans with Fanconi anemia who carry the mutated gene. Specifically, the loss of Brca2 led to defective DNA repair and the accumulation of mutations in the so-called progenitor cells that give rise to many regions of the nervous system. This resulted in small brain size due to apoptosis of the abnormal cells.















These findings showed that the mouse model closely copied the human characteristics of Fanconi anemia and could become a valuable tool for studying the cause and treatment of this disease.


Researchers also discovered that another gene, ATM, plays a secondary but important role in protecting the developing nervous system by triggering apoptosis in cells that have stopped dividing but still contain DNA damage. ATM prevents these abnormal cells, called granule precursors, from becoming incorporated into the developing cerebellum. In this way, ATM plays a backup role in further ensuring normal gene function after the period of rapid growth is complete.


The St. Jude team demonstrated the role of Brca2 in the developing mouse nervous system using a laboratory technique called conditional gene inactivation. This process eliminated the gene from the nervous system, but left it intact in the rest of the body. The use of this technique was important because previous studies showed that mouse embryos cannot develop when the gene is absent from all the cells of the body. The team observed how the specific loss of Brca2 activity from the nervous system affected its embryonic and postnatal development. The finding helps explain how rapidly dividing cells in the developing cerebellum identify and repair errors in the DNA that occur during the duplication of chromosomes before cell division occurs.


"Our work is a significant step in understanding the interplay of genes linked to DNA repair and their role in preventing disease," said Pierre-Olivier Frappart, Ph.D., a postdoctoral researcher in McKinnon's laboratory, who did much of the work on this project. "As more mouse models lacking specific genes in certain tissues become available, we'll be able to further determine the relationships among various DNA repair pathways during the development of the nervous system."


Other authors of the report include Youngsoo Lee and Jayne Lamont (St. Jude).


This work was supported in part by the National Institutes of Health, a Cancer Center Support Grant and ALSAC.

Wide Range Of Tissue Types Produced Using Stem Cells Derived From Adult Testes

After a decade of research, Howard Hughes Medical Institute scientists have succeeded in reprogramming adult stem cells from the testes of male mice into functional blood vessels and contractile cardiac tissue. The research offers a promising new source of stem cells for use in organ regeneration studies.



Some scientists think that organ-specific adult stem cells may offer the same therapeutic potential as embryonic stem cells, without the ethical concerns or the risk of immune rejection that are associated with embryonic stem cell therapies. However, adult stem cells may lack the plasticity and pluripotency of embryonic stem cells' capacity to generate any cell type. The study of adult stem cells has also been limited by their relative scarcity in various organs and the attendant difficulties in identifying and harvesting them, as well as differentiating them in large quantities into functional vascularized tissues.



HHMI investigator Shahin Rafii and his colleagues at Weill Cornell Medical College appear to have solved some of these problems in male mice. Using spermatogonial progenitor cells obtained from the mouse's testes, the researchers reprogrammed the cells to form multipotent adult spermatogonial-derived stem cells. If the same can be done with human cells, they say, adult stem cells may be a promising source of new therapies for men, for diseases such as vascular diseases, heart disease, Alzheimer's, Parkinson's, stroke, diabetes, and even cancer.



Scientists have had good success in deriving pluripotent stem cell lines -- those with the ability to develop into multiple cell types -- from adult testes cells. But only a small subset of cells from the testes has the potential to become pluripotent, and until now, investigators have lacked a means to identify and isolate them.



In a paper published online in the journal Nature, Rafii and colleagues at Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center report that they have identified a novel cell surface marker that is expressed on a unique set of cells within adult testes known as the spermatogonial stem and progenitor cells (SPCs). The marker, GPR125, enabled the scientists to identify and harvest a large number of SPCs from adult mouse testes, then propagate and reprogram them in the lab to become stem cells that could differentiate into many cell types.



The researchers demonstrated that these multipotent adult spermatogonial-derived stem cells (MASCs) could develop in vivo into working blood vessel (endothelial) cells and tissue, as well as contractile cardiac tissue, brain cells, and a host of other cell types. They also injected MASCs from culture into mouse blastocysts -- embryonic cells -- that they implanted in mature female mice. When the blastocysts developed into mice, the researchers could see that the MASCs had differentiated into many kinds of tissue. These data suggested that the MASCs are truly multipotent: reprogrammable to differentiate into functional tissues.
















Ten years ago, Rafii observed that human testicular cancer cells share many characteristics with adult stem cells. As an oncologist, he also noticed that a large number of patients with testicular cancer develop tumors called teratomas, which contain different types of tissue. Based on these observations, he reasoned that spermatogonia, whose sole function is to generate the precursors to sperm, have the potential to readily give rise to pluripotent cells. As such, he thought, they might prove more amenable to reprogramming than other adult stem cells.



Using gene screening studies, Rafii and colleagues discovered a potential specific surface marker on SPCs. Comparison of all cells in the adult testis showed that this G-protein coupled receptor, known as GPR125, was expressed on SPCs, but not other mature germ cells. With GPR125 in hand, Rafii could isolate large numbers of SPCs from adult mouse testes.



They also established a highly sophisticated culture system in which the progenitor cells rapidly grow and divide, creating a large population of cells that can be converted into MASCs.



"It appears that these specialized GPR125-positive spermatogonial cells could be an easily obtained and manipulated source of stem cells with a similar capability to form new tissues that we see in embryonic stem cells," said Rafii. For male patients, he believes, "It could someday mean a readily available source of stem cells that gets around ethical issues linked to embryonic stem cells. It also avoids issues linked to tissue transplant rejection, since these autologous cells come from the patient's own body."



Rafii's team is currently pursuing a similar study of human testes to determine whether stem cells derived from their spermatogonial progenitor cells share the pluripotency of the mouse MASCs. "We believe this to be an easily obtainable goal in the near future," he said.



If they succeed, several steps remain before such stem cells could be applicable to humans. "We still have to learn the exact biochemical and epigenetic 'switch' that tells GPR125-positive SPCs to convert into MASCs," said Marco Seandel, a senior post-doctoral fellow in Rafii's laboratory who is the first author of the Nature paper. "Discovering that switch will be crucial to our being able to create MASCs on demand,"



There is a chance that implanted cells derived from MASCs may trigger cancer in the recipient. This is an area that requires further investigation, Rafii said. However, he noted, "So far, we haven't seen any cancer or evidence of pro-cancerous activity in adult mice that are implanted with differentiated MASC cell tissue derivatives."



Rafii and his team have worked out the growing conditions that coax spermatogonial progenitor cells to develop into MASC germ lines -- genetically stable stem cells that continue reproducing indefinitely. Stem cell studies have been limited to date by the scarcity of germ cell lines. "None of these GPR125-positive germ cell lines was previously readily available for genetic, biochemical, and cellular analysis by other laboratories," says Rafii. "We intend to share them with other researchers."



Rafii's lab is now investigating whether GPR125 can be used to isolate cells from other adult tissues that can be converted into multipotent stem cells. His group has also begun pursuing a similar effort in ovaries. "It's much more difficult," he said. "However, it is possible that reprogrammable stem cells with similar properties to GPR125-positive SPCs may also exist, although at very low numbers, in adult mouse or human ovaries." His lab is actively investigating this intriguing possibility, Rafii said.







Source: Jim Keeley


Howard Hughes Medical Institute

Diabetic Women At Increased Risk Of Vascular Disease

Diabetes is associated with the development of vascular (blood vessel) disease. As we age, vascular disease becomes more common. It has been thought that females may be more susceptible to the earlier development of vascular disease, as vascular changes are observed in females long before any significant development occurs in males. Now, a team of Georgetown University researchers has determined that the vascular activities in diabetic animals vary according to sex. This discovery may eventually have implications for the way males and females are treated medically in the future.



The Study



The study, entitled "Sex Differences in Response to Vasoactive Substances in Early Uncontrolled Diabetes," was conducted by Adam Mitchell, Adam Myers and Susan Mulroney, all of the Department of Physiology and Biophysics, Georgetown University, Washington, DC. Mr. Mitchell presented the status of the team's findings at the conference, Sex and Gender in Cardiovascular-Renal Physiology and Pathophysiology. The meeting was sponsored by the American Physiological Society (APS; the-aps/).



The Study



The researchers examined the notion that very early changes in artery activity exists in diabetic animals and differ by sex. To test their hypothesis they divided adult male and female rats into three groups. The first group (control) received no treatment. The second group received streptozotocin (STZ) to induce diabetes. The third group received STZ plus growth hormone (GH), which is thought to exacerbate disease progression in diabetes.



After eight weeks, the vascular reactivity to phenylephrine, which increases blood pressure, and acetylcholine, which reduces blood pressure, was measured in the vessels from the animals. Vascular response to these substances was also observed during exposure to L-NAME (which blocks production of nitric oxide, a potent artery relaxer) and neuropeptide Y (which augments the restriction of blood vessels).



The investigators found that:



* in the early stage of the disease, both male and female diabetics experienced significant decreases in the reactivity (i.e., how responsive the vessel is to a drug) of their blood vessels when exposed to acetylcholine. This occurred independent of the GH injections.



* while female diabetic rats had an increased response to phenylephrine, there was no such change among their male counterparts.



* female controls had a larger change in phenyleprine reactivity in the presence of L-NAME than did diabetic females, indicating that the diabetic females had a reduced level of nitric oxide, which dilates the artery and increases blood flow.



* diabetic males had the opposite reaction of diabetic females when exposed to phenylephrine and L-NAME. The diabetic males also produced more nitric oxide than did their controls.



* all diabetic rats exposed to growth hormone showed an increase in nitric oxide, regardless of gender.



Conclusions



The findings support the researchers' hypothesis of the existence of sex-related changes in vascular activity in diabetic animals. While the production of NO is significantly altered in the diabetic rats, the results show that gender and the presence of GH greatly contribute to this vascular dysfunction. According to Mitchell, "These findings show the importance of sex differences to understanding development of vascular problems early in diabetes and has implications on potential sex-specific therapeutic intervention."







The American Physiological Society (APS; the-aps/) has been an integral part of the scientific discovery process since it was established in 1887. Physiology is the study of how molecules, cells, tissues and organs function to create health or disease.



Source: Donna Krupa


American Physiological Society

Missing Molecules Hold Promise Of Therapy For Pancreatic Cancer

By determining what goes missing in human cells when the gene that is most commonly mutated in pancreatic cancer gets turned on, Johns Hopkins scientists have discovered a potential strategy for therapy.


The production of a particular cluster of genetic snippets known as microRNAs is dramatically reduced in human pancreatic tumor cells compared to healthy tissue, the researchers report in a study published Dec. 15 in Genes and Development. When the team restored this tiny regulator, called miR-143/145, back to normal levels in human pancreatic cancer cells, those cells lost their ability to form tumors.


"Our finding that these specific microRNAs are downstream of the most important oncogene in pancreatic cancer sets the stage for developing methods to deliver them to tumors," says Josh Mendell, M.D., Ph.D., an associate professor in the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, and an early career scientist of the Howard Hughes Medical Institute. "When we restore microRNAs to cancer cells in which their levels are repressed, the cells no longer are tumorigenic. We have every reason to believe that the efficient delivery of miR-143/145, if achievable, would be therapeutically beneficial."


The team focused its investigation on KRAS, a member of the important RAS family of oncogenes that is mutated in almost all cases of the most common form of pancreatic cancer.


The researchers conducted their studies in a multitude of model systems human cells growing in culture as well as those harvested directly from tumors, and also in mice and zebrafish. First, using cell lines derived from pancreatic tumors and growing in culture, they added gene products such as mutant KRAS and an inhibitor of mutant KRAS, and then measured the microRNA responses. Next, they conducted the same experiments using cells from patients' pancreatic tumors. Finally, they looked at pancreatic tissue from mice and zebrafish to see what happened when KRAS was activated.


Every time, the team noted the same robust findings. When KRAS was activated, the microRNA cluster miR-143/145 was powerfully repressed, to a fraction of the levels in normal, non-cancerous cells. Restoring the expression of miR-143/145 back to the level of normal cells was sufficient to confer "a very striking change in behavior of those cells," Mendell says. When human pancreatic cancer cells with low microRNA levels were injected into mice, they formed tumors within 30 days. However, when the team restored the levels of microRNAs to the levels of normal cells and injected them into mice, tumors failed to form.


"Our findings showed that repression of the miR-143/145 microRNA cluster is a very important component of the tumor-promoting cellular program that is activated when KRAS is mutated in cancer cells," says Oliver Kent, a postdoctoral fellow in the Mendell laboratory and first author on the paper.















At some point in the process of a normal cell evolving into a tumor cell, it loses microRNAs. When the KRAS gene is mutated a common event in pancreatic cancer it somehow purges cells of miR-143/145, the cluster of microRNAs that normally put the brakes on tumorigenesis.


"It is likely that some microRNAs will have very broad antitumorigenic effects in many different types of cancers," says Mendell, whose lab is building animal models to investigate how different microRNAs participate in different tumor types. "In fact, there is already evidence that miR-143/145 can suppress other types of tumors such as colon and prostate cancer. On the other hand, the effects of some microRNAs will likely be very tumor-specific."


Merely 22 nucleotides in length, microRNAs are enigmatic bits of genetic material that, despite being pint-sized, apparently are mighty. This field of study is less than a decade old; scientists still don't have a good grasp on the fundamental role of microRNAs in normal biology.


"We need a better understanding of their basic functions to more fully understand how microRNAs participate in diseases," Mendell says.


Having studied microRNAs in the context of several types of cancer, Mendell says delivery remains a major issue for nucleic acid-based therapies.


"There is a lot of work going on to develop ways to deliver microRNAs to different tissue sites," Mendell says. "I'm optimistic that the liver and even the pancreas will become accessible to these types of therapies and benefit from them."


In addition to Joshua Mendell and Oliver Kent, authors of the paper are Raghu R. Chivukula, Michael Mullendore, Erik A. Wentzel, Georg Feldmann, Kwang H. Lee, Shu Liu, Steven D. Leach and Anirban Maitra, all of Johns Hopkins.


The research was supported by the Howard Hughes Medical Institute, the Lustgarten Foundation for Pancreatic Research, the Sol Goldman Center for Pancreatic Cancer Research, the Michael Rolfe Foundation for Pancreatic Research and the National Institutes of Health.


Source: Johns Hopkins Medicine

Rare Tumor Cells In Bloodstream Can Now Be Detected By Microchip-Based Device

A team of investigators from the Massachusetts General Hospital (MGH) Biomicroelectromechanical Systems (BioMEMS) Resource Center and the MGH Cancer Center has developed a microchip-based device that can isolate, enumerate and analyze circulating tumor cells (CTCs) from a blood sample. CTCs are viable cells from solid tumors carried in the bloodstream at a level of one in a billion cell. Because of their rarity and fragility, it has not been possible to get information from CTCs that could help clinical decision-making, but the new device - called the "CTC-chip,"- has the potential to be an invaluable tool for monitoring and guiding cancer treatment.



"This use of nanofluidics to find such rare cells is revolutionary, the first application of this technology to a broad, clinically important problem," says Daniel Haber, MD, director of the MGH Cancer Center and a co-author of the report in the December 20 issue of Nature. "While much work remains to be done, this approach raises the possibility of rapidly and noninvasively monitoring tumor response to treatment, allowing changes if the treatment is not effective, and the potential of early detection screening in people at increased risk for cancer."



The existence of CTCs has been known since the mid-19th century, but since they are so hard to find, it has not been possible to adequately investigate their biology and significance. Microchip-based technologies have the ability to accurately sense and sort specific types of cells, but have only been used with microliter-sized fluid samples, the amount of blood in a fingerprick. Since CTCs are so rare, detecting them in useful quantities requires analyzing samples that are 1,000 to 10,000 times larger.



To meet that challenge the MGH BioMEMS Resource Center research team - led by Mehmet Toner, PhD, senior author of the Nature report and director of the center in the MGH Department of Surgery, and Ronald Tompkins, MD, ScD, chief of the MGH Burns Unit and a co-author - first investigated the factors required for microchip analysis of sufficiently large blood samples. The device they developed utilizes a business-card-sized silicon chip, covered with almost 80,000 microscopic posts coated with an antibody to a protein expressed on most solid tumors. The researchers also needed to calculate the correct speed and force with which the blood sample should pass through the chip to allow CTCs to adhere to the microposts.



"We developed a counterintuitive approach, using a tiny chip with critical geometric features smaller than a human hair to process large volumes of blood in a very gentle and uniform manner - almost like putting a 'hose' through a microchip," explains Toner.



Several tests utilizing cells from various types of tumors verified that CTCs were captured by posts covered with the antibody 'glue.' Even tumor cells expressing low levels of the target protein and samples containing especially low levels of CTCs were successfully analyzed by the CTC-chip. In contrast to current technology for detecting CTCs, the new microchip device does not require any pre-processing of blood samples, which could damage or destroy the fragile CTCs.
















The researchers then tested the CTC-chip against blood samples from 68 patients with five different types of tumors - lung, prostate, breast, pancreatic and colorectal. A total of 116 samples were tested, and CTCs were identified in all but one sample, giving the test a sensitivity rating of 99 percent. No CTCs were found in samples from cancer-free control volunteers. To evaluate the device's ability to monitor response to treatment, blood samples were taken from nine cancer patients during their treatment for lung, colorectal, pancreatic or esophageal tumors. Changes in levels of CTCs accurately reflected changes in tumor size as measured by standard CT scans.



"We looked at four major cancer killers and were able to consistently find these cells and correlate test results with traditional monitoring techniques," Toner says. "Some of these tumors have several potential drugs to choose from, and the ability to monitor therapeutic response in real time with this device - which has an exquisite sensitivity to CTCs - could rapidly signal whether a treatment is working or if another option should be tried."



CTCs also can provide the molecular information needed to identify tumors that are candidates for the new targeted therapies and should help researchers better understand the biology of cancer cells and the mechanisms of metastasis. Considerable work needs to be done before the CTC-chip is ready to be put to clinical use, and the MGH investigators are establishing a Center of Excellence in CTC Technologies to further explore the potential of the device, which also has been licensed to a biotechnology company for commercial development.






The research was funded by grants from the National Institutes of Health and a Doris Duke Distinguished Clinical Scientist Award. The paper's co-lead authors are Sunitha Nagrath, PhD, of the MGH BioMEMS Resource Center, and Lecia Sequist, MD, MGH Cancer Center. Additional co-authors are Shyamala Maheswaran, PhD, Daphne Bell, PhD, Lindsey Ulkus, Matthew Smith, MD, PhD, Eunice Kwak, MD, PhD, Subba Digumarthy, MD, Alona Muzikansky, and Paula Ryan, MD, MGH Cancer Center; and Daniel Irimia, MD, PhD, and Ulysses Balis, MD, MGH BioMEMS Resource Center.



Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.



Source: Sue McGreevey


Massachusetts General Hospital

Scientists Discover Molecular Pathway For Organ Tissue Regeneration And Repair

Scientists have discovered a molecular pathway that works through the immune system to regenerate damaged kidney tissues and may lead to new therapies for repairing injury in a number of organs.


The findings, reported in this week's Proceedings of the National Academy of Sciences (PNAS), come from collaborative research led by Cincinnati Children's Hospital Medical Center and the Brigham & Women's Hospital of Harvard Medical School.


The study may have significant medical ramifications as currently there are no effective treatments for acute kidney injury a growing problem in hospitals and clinics, according to the study's senior co-authors, Richard Lang, Ph.D., a researcher in the divisions of Pediatric Ophthalmology and Developmental Biology at Cincinnati Children's, and Jeremy Duffield, M.D., Ph.D., a researcher at Brigham and Women's Hospital. Acute kidney injury is a significant cause of kidney disease, cardiovascular complications and early death, affecting as many as 16 million children and adults in the United States.


The molecular repair pathway involves white blood cells called macrophages part of the immune system that respond to tissue injury by producing a protein called Wnt7b. Scientists identified the macrophage-Wnt7b pathway during experiments in mice with induced kidney injury. Wnt7b is already known to be important to the formation of kidney tissues during embryonic organ development. In this study the scientists found the protein helped initiate tissue regeneration and repair in injured kidneys.


"Our findings suggest that by migrating to the injured kidney and producing Wnt7b, macrophages are re-establishing an early molecular program for organ development that also is beneficial to tissue repair," said Dr. Lang. "This study also indicates the pathway may be important to tissue regeneration and repair in other organs."


Wnt7b is part of the Wnt family of proteins, which are known to help regulate cells as they proliferate, grow and become specific cell types for the body. Wnt proteins have also been linked to the regulation of stem cells in bone marrow and skin, which suggested to researchers of the current study that Wnt might have a role in tissue regeneration.


The researchers conducted a number of experiments of kidney injury in mice to identify the repair pathway, finding that:



-- Silencing macrophage white blood cells through a process called ablation reduced the response level of Wnt proteins to injured kidney cells.



-- Deleting the Wnt7b protein from macrophages diminished normal tissue repair functions in injured kidneys.



-- Injecting into the injured kidneys a protein calked Dkk2, which is known to help regulate the Wnt pathway during embryonic development, enhanced the macrophage-Wnt7b repair process. This also restored epithelial surface cells that line internal kidney surfaces and suggested a therapeutic potential for the pathway.


Drs. Lang and Duffield said the repair pathway may benefit other injured organs because macrophages act somewhat like a universal emergency responder in the body, rushing to injured tissues wherever damage occurs. Another factor is the central role the Wnt pathway plays in cell regulation and function throughout the body.


Other collaborating institutions in the study include: the Department of Structural Biology, St, Jude Children's Hospital, Memphis, Tenn.; the departments of Internal Medicine and Molecular Biology, University of Texas Southwest Medical Center; Department of Molecular and Developmental Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y.; Department of Molecular and Cellular Biology, Harvard University; the Visual Systems Group in the division of Pediatric Ophthalmology at Cincinnati Children's; and the Department of Ophthalmology, University of Cincinnati.


Funding support came from the National Institutes of Health, the American Society of Nephrology Gottschalk Award, the Genzyme Renal Initiatives Program, a National Taiwan Merit Award, and the Abrahamson Pediatric Eye Institute Endowment at Cincinnati Children's.


Source: Cincinnati Children's Hospital Medical Center

Rensselaer Professor Utilizing New York State Grant To Study Adult Stem Cells

Rensselaer Polytechnic Institute Assistant Professor of Biomedical Engineering Deanna Thompson is utilizing more than $300,000 in New York state funding as part of the state stem cell research program, NYSTEM, to study adult neural stem cells. The NYSTEM program is New York's $600 million publicly funded grant program to advance scientific discovery in the area of stem cells.


Working at the interface of engineering and neuroscience, her research is helping scientists and doctors develop new stem cell therapies and research tools utilizing these important cells. The adult stems cells she is investigating could play an important role in understanding and treating a variety of brain illnesses, from cancer and Alzheimer's to traumatic brain injury and stroke.


"Dr. Thompson is a young, rising star in her field and has come up with a highly innovative approach to direct, cause, and control nerve regeneration through stem cell bioengineering," said Rensselaer Biomedical Engineering leader Deepak Vashishth. "The results of her NYSTEM-funded research will provide unique insight into the stem cell niche and help develop new tools and therapies for regenerative medicine."


Neural stem cells are a specialized type of stem cell that can be found in the adult nervous system. These stem cells have the potential to repair or replace damaged nerve cells. For researchers, the ability to generate new cells or repair damaged nerve cells would be exceptionally helpful to heal a traumatic brain injury following an accident or reverse the cellular death caused by an illness like Parkinson's disease. Thompson's research is working to understand exactly how neural stem cells proliferate or differentiate into new nerve cells in the brain so that ability can be replicated to develop new medical treatments.


In order to control stem cell fate or differentiation, she must first understand the complex environment surrounding the stem cells. This environment or "niche" contains vascular and other cells, proteins, carbohydrates, and other cell products. In this niche, stem cells multiply in an orderly manner and can differentiate into new nerve cells or other non-nerve cells in the brain known as glia. Without the key control elements of the niche, a stem cell might multiply quickly, turning from a promising cure to a cancerous tumor. Without a clear understanding of the stem cell niche, a medical treatment involving stem cells could be very risky.


An element of the stem cell niche that Thompson is studying with this round of NYSTEM funding is endothelial cells. These cells line the interior of blood vessels, which are highly concentrated in the regions of the brain where neural stem cells reside. In particular, Thompson is looking at how materials produced by endothelial cells during their development influence neural stem cells' fate. According to Thompson, such control could allow for the development of stem cell therapies grown from an individual patient's own neural stem cells.















To perform her research, Thompson will utilize the resources of the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer.


"Deanna's work, which is at the interface of cell biology and materials science, epitomizes the interdisciplinary research within CBIS," said CBIS Director and the Howard P. Isermann '42 Professor of Chemical and Biological Engineering Jonathan Dordick. "By studying the physiology and function of adult stem cells in a synthetic niche, Deanna has identified key determinants of neuronal cell growth and differentiation. Her work has impacted the burgeoning field of regenerative medicine and has helped CBIS make a name for itself in this critical research area."


Her work with brain cells has several other important implications beyond stem cell therapies. Another facet of her research as a member of National Science Foundation-funded Rensselaer Nanoscale Science and Engineering Center for Directed Assembly of Nanostructures involves the use of nanotechnology to repair damaged nerves in the brain and spinal cord.


"Professor Thompson's work in the Center for Directed Assembly of Nanostructures has addressed both the use of nanotubes in directing neuron growth and investigated the toxicity of carbon nanotubes in potential new medical therapies," said Linda Schadler, associate dean for academic affairs in the School of Engineering and professor in the Department of Materials Science and Engineering. "The ability to direct neuron growth is exciting in terms of helping patients repair damaged nerves. Through her work, she was also one of the first to recognize the role of glial cells in neuron growth, which may be the key to bringing this exciting technology to fruition."


Source: Rensselaer Polytechnic Institute (RPI)

The Consortium For Neuropsychiatric Phenomics Funded By NIH

The National Institutes of Health has awarded $22.5 million to a team of scientists centered at the Semel Institute for Neuroscience and Human Behavior at UCLA to fund the Consortium for Neuropsychiatric Phenomics (CNP), an interdisciplinary, campuswide effort to understand the biology underlying a variety of mental disorders.



Phenomics is the study of an organism's full complement of phenotypes -- those manifest characteristics, ranging from single proteins to anatomical traits and complex behaviors, that result from the organism's genetic makeup and environment, said Robert Bilder, UCLA professor of psychiatry and director of the new consortium. Understanding an organism's phenotype is the next logical step following the recent decoding the human genome. That decoding effort, which discerned the DNA sequences that form the basic instructions for biological processes, was designed to enable the identification of genetic variations responsible for the major diseases that plague humankind.



Phenomics takes a more "holistic viewpoint," Bilder said. "To understand how these genetic variations are associated with disease now requires the decoding of the human phenome, the sum of the physical and behavioral manifestations of those genetic variations and how they interact with the environment.



"Understanding the fundamental biological bases of neuropsychiatric disease -- from the molecule to the mind -- is an enormous challenge and will offer a grand challenge to biomedical research for the rest of the century," he said.



Currently, psychiatrists do not possess the types of laboratory tests or biological models that can be useful in studying these disorders, Bilder said.



"The diagnostic systems we have in place are widely acknowledged to be flawed, because the phenotypes we have are not based on research but are descriptive," he said. "That is, they are based on symptoms we usually learned about, ironically, from asking patients who have disorders that make communication difficult.



"We so far lack markers to identify more fundamental deficits," he said. "We need to drill down and get closer to the specific level where a gene might be responsible for the process."



That is the goal of the consortium, which will target the behavioral and cognitive functions thought to underlie such neuropsychiatric syndromes as schizophrenia, bipolar disorder and attention deficit hyperactivity disorder.



In a departure from science-as-usual, the consortium will aim to discover the underpinnings of basic, healthy functioning systems -- such as memory and impulse control -- rather than concentrating on the genetic anomalies that may be associated with the neuropsychiatric disorders themselves. By focusing on these healthy brain systems, the researchers hope to accelerate the discovery of genes that are relevant to mental disorders and to find new treatments.
















Employing a broad approach to attacking this problem, the consortium team comprises 52 investigators, many affiliated with the Semel Institute but cutting widely across campus disciplines as well, with members from the fields of psychiatry, neurology, neurobiology, human genetics, psychology and computer science collaborating and sharing data. Subawards will support research in Finland (at the universities of Helsinki and Oulu), at the University of California, Santa Barbara, and at the Medical University of South Carolina.



This interdisciplinary approach is a major goal of the consortium, which is one of nine nationwide being funded by the NIH's Roadmap for Medical Research program. The Roadmap program is designed not only to address health challenges that have been resistant to traditional research approaches but to fundamentally change how research is conducted, by integrating a wide range of disciplines to attack a problem. As opposed to multidisciplinary research, which involves teams of scientists approaching a problem from within their own disciplines, interdisciplinary research integrates elements from a wide range of disciplines, often including basic and clinical research, behavioral biology, and social sciences, so that all of the scientists may approach the problem in a new way.



"The interdisciplinary research programs within the Roadmap embody a central goal of this program -- to help transform the way research is conducted," said Dr. Elias A. Zerhouni, NIH director. "These programs are designed to encourage and enable change in academic research culture to make interdisciplinary research easier to conduct for scientists who wish to collaborate in unconventional ways."



"Our team is thrilled to have this opportunity to forge a unique path in neuropsychiatry research," Bilder said. "Many scientists and clinicians already acknowledge major limitations in the current system for diagnosing and treating patients. We believe the CNP strategy strongly complements existing approaches and offers new hope for discovery."







For more information about the consortium, visit phenomics.ucla/.



Source: Mark Wheeler


University of California - Los Angeles

Study Of Malaria Parasite Invasion Focuses On Importance Of Sugars

Researchers at the Johns Hopkins Malaria Research Institute (JHMRI) have identified a sugar in mosquitoes that allows the malaria-causing parasite, Plasmodium falciparum, to attach itself to the mosquito's gut. Invasion of the midgut cell layer is an essential stage in the parasite's lifecycle and in the transmission of malaria from mosquitoes to humans. By reducing the level of the sugar, chondroitin sulfate, in the mosquito, the researchers prevented 95 percent of the parasites in the mosquito from attaching to the gut, thus blocking its development. The study is published in the online Early Edition of Proceedings of the National Academy of Sciences (PNAS).



"This study provides significant new insights on how the parasite develops in the mosquito, complementing our earlier identification of another parasite midgut receptor that is a target for a transmission-blocking vaccine," said Marcelo Jacobs-Lorena, PhD, senior author of the study and a professor in the Bloomberg School's W. Harry Feinstone Department of Molecular Microbiology and Immunology. "This line of research could lead to new approaches for interfering with the spread of this deadly disease."



To determine whether the parasite utilizes chondroitin glycosaminoglycans to invade the mosquito midgut cells, the researchers used a process known as RNA interference to inhibit production of a mosquito enzyme that is needed to produce chondroitin sulfate. With the sugar removed, parasite adhesion and midgut invasion were substantially decreased.



"Our study highlights the importance of sugars in parasite invasion of the mosquito gut. Previously, this phenomenon was only observed during parasite invasion of human tissues," said Rhoel R. Dinglasan, PhD, MPH, lead author of the study and a postdoctoral fellow with the Malaria Research Institute. "It appears as if the parasite's use of sugars as a strategy for cell invasion of tissues is similar in both man and mosquito. This may be an Achilles' heel for the parasite, opening up the possibility of developing a vaccine that works against all stages of the parasite's lifecycle."



According to the researchers, many important questions must still be answered to determine if the glycosaminolgycan identified could be a potential antigen for a transmission-blocking vaccine. In a study published earlier this year in the PNAS, the JHMRI team identified a previously unknown mosquito antigen that the parasite uses for entry into the mosquito midgut, a critical step in the Plasmodium parasite's development. The researchers produced an antibody that acts as a blanket to prevent the parasite from accessing the mosquito midgut antigen.



Their research showed that the antibodies were effective against multiple malaria parasites and could potentially provide the basis for a future 'universal' malaria transmission-blocking vaccine.







Additional authors of "Plasmodium falciparum ookinetes require mosquito midgut chondroitin sulfate proteoglycans for cell invasion," are Aditi Alaganan, Anil K. Ghosh, Akio Saito and Toin H. van Kuppevelt.



The research was supported by the Ruth L. Kirschstein Research Service Award in addition to other grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health.



The Malaria Research Institute at the Johns Hopkins Bloomberg School of Public Health was founded in 2001 as a state-of-the-art research facility that would mount a broad program of basic-science research to treat and control malaria, develop a vaccine and find new drug targets to prevent and cure this deadly disease. Information about JHMRI is available at malaria.jhsph/.



Source: Tim Parsons


Johns Hopkins University Bloomberg School of Public Health

Functional Group Diversity Of Bee Pollinators Increases Crop Yield

In a study on the functional role of biodiversity in tropical agroforestry systems, we found that pollinator diversity, but not abundance, was positively related to seed set of pumpkin.

Furthermore, we classified species due to differences in spatiotemporal resource use and within-flower behaviour into functional guilds and showed that diversity of functional groups explained more variance in seed set than did species richness, highlighting the role of functional complementarity.

These results enhance our understanding of how pollinator diversity affects food production and how losses of bee species and functional diversity under global change threaten sustainable crop production.


Proceedings of the Royal Society B: Biological Sciences


Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.


publishing.royalsociety/proceedingsb

iPlant Collaborative Will Unite Scientists Across Disciplines

Cold Spring Harbor Laboratory (CSHL) will play a central role in an important new initiative called the iPlant Collaborative, funded by the National Science Foundation (NSF). The Collaborative will define and address "grand challenge questions" in plant biology that have global implications.



"The idea is to develop an all-encompassing computer- and internet-based infrastructure that will transform the way plant science is done, and that will be accessible, at different levels, by scientists across the disciplines and across the planet," explained Lincoln Stein, Ph.D., CSHL professor and a co-principal investigator of the Collaborative. "In addition, the program will be a valuable resource for students and interested members of the public."



CSHL and four research universities, led by the University of Arizona, will share a $50 million NSF grant over five years to launch the iPlant Collaborative. It will bring together researchers from every area within plant biology - molecular and cellular biologists, geneticists, genome scientists, as well as experts on ecosystems and biosystem diversity - by building infrastructure through which they can more readily interact and collaborate.



Since research is done in real-time as well as "offline" in conjunction with mathematicians, computer scientists and engineers, informatics experts, and even social scientists, plant biologists can be certain that the tools available through the iPlant network will reflect the latest knowledge. "This reflects the way science is done in the 21st century," says Rob Martienssen, Ph.D., professor and head of plant genetics at CSHL. "The days have long passed when it made sense for individual scientists, or individual labs, or even individual institutions, to attack major scientific questions in isolation from the broader community."



Collaboration across disciplines in pursuit of innovative science - for instance, plant genome experts working side-by-side with mathematicians and statisticians to interpret the results of innovative microarray scans of genomic mutations designed by biosystems engineers - is already the norm in the plant science community and throughout the life sciences.



"But," emphasizes Dr. Stein, whose bioinformatics tools are widely used by genome scientists worldwide, "the dimension that is lacking, and which the Collaborative seeks to address, concerns the forging of a functional community, within the discipline and extending to those in computer science, math and other fields, upon whose expertise plant science depends."



CSHL, through its Dolan DNA Learning Center (DNALC), will collaborate with the project team to embed outreach materials within the iPlant portal, thus tightly linking plant research and education. Such material will include video and audio podcasts to publicize the project and to provide students and teachers a window on the "grand challenge" development process.



The DNALC will work with plant researchers to develop video interviews and narrated animations that explain the conceptual background and historical development of each "grand challenge." The culmination of which will spawn a nationwide program that will train 1,000 science teachers in how to utilize iPlant tools for student projects that support integrative and computational thinking.
















"Science education and public outreach typically begin well after a scientific revolution has settled down into what Thomas Kuhn called normal science. In this project, we want to directly involve students and teachers in this revolutionary period of plant research by providing them with educational interfaces into the same data used by iPlant scientists," stated David Micklos, Ph.D., Executive Director of the DNALC.



The iPlant Collaborative was formed after a call for proposals in 2006 from the NSF's Department of Biological Infrastructure. CSHL will host the Collaborative's inaugural meeting, set for April 2008, as well as additional meetings throughout the five-year period of the NSF grant.



"It's an exciting prospect that brings to mind some other forward-looking moments in the recent history of biological research in which CSHL was deeply involved," said Dr. Martienssen. "It was on our campus that the idea for sequencing the first plant genome got off the ground, and where the outlines of what became the Human Genome Project were first sketched. We are hoping that the iPlant Collaborative will also achieve great things."







CSHL is a private, non-profit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering.



For more information, visit cshl/.



Source: Jim Bono


Cold Spring Harbor Laboratory

News Tips From The Journal Of Neuroscience

1. Sorting Out Membrane-Initiated Estrogen Effects

Marissa I. Boulware, Holly Kordasiewicz, and Paul G. Mermelstein



The caveolins (CAV1-3) are, not surprisingly, integral components of caveolae, pockets within the plasma membrane capable of signal transduction. In this week's Journal, Boulware et al. describe two distinct estrogen receptor signaling pathways that require caveolins, thus providing a potential mechanism for the membrane effects of estrogens. In the first, activation of membrane-localized estrogen receptor a (ERa) led to activation of metabotropic glutamate receptor 1a (mGluR1a). That signal culminated in mitogen-activated protein kinase (MAPK)-dependent phosphorylation of the cAMP response element-binding protein (CREB). In cultured hippocampal neurons, a point mutation in ERa that disrupted its association with CAV1 impaired estradiol activation of mGluR1a and CREB phosphorylation. Signaling was also abolished by a dominant-negative CAV1. In a second estradiol-activated pathway, binding at ERa or ERГџ triggered mGluR2/3 activation, which attenuated L-type calcium channel-dependent CREB phosphorylation. This independent signaling process was not affected by the loss of ERa or CAV1 but was eradicated by loss of CAV3.



2. A SUMO E3 Ligase and Dendritic Morphogenesis

Aryaman Shalizi, Parizad Bilimoria, Judith StegmГјller, Brice GaudilliГЁre, Yue Yang, Ke Shuai, and Azad Bonni



The terminal dendrites of cerebellar granule cells mature from smooth "cups" into the serrated dendritic "claws," which receive input from mossy fiber terminals and Golgi cell axons. This week, Shalizi et al. examined the underlying signaling mechanisms in dendritic morphogenesis. Claw differentiation requires the transcription factor myocyte enhancer factor 2A (MEF2A) in a form that was modified by linkage of a small ubiquitin-related modifier (SUMO). The final step in sumoylation is carried out by a SUMO E3 ligase. The authors demonstrated that the E3 ligase PIASx (protein inhibitors of activated STAT) led to SUMO modification of MEF2A and repression of MEF2-dependent transcription. After knockdown of PIASx expression with RNA interference, claw structures were reduced in dendrites of developing rat cerebellar cortex, whereas overexpression of PIASx increased claws. Expression of sumoylated MEF2A rescued claw differentiation in the absence of PIASx.



3. Getting at the Itch

Steve Davidson, Xijing Zhang, Chul H. Yoon, Sergey G. Khasabov, Donald A. Simone, and Glenn J. Giesler Jr.



You don't need to be a neuroscientist to know that antihistamines can block itch. However, this week Davidson et al. examined cowhage, the lesser-known, nonhistaminergic itch producer. The authors report that it activated a different set of sensory-processing neurons than histamine. Cowhage is contained in tiny spicules, or hairs, covering the pods of the aptly named tropical legume Mucuna pruriens. The authors compared responses of primate ascending spinothalamic tract (STT) neurons to histamine and cowhage applied to receptive fields on the hairy skin. Units were classified as either wide dynamic range (WDR) or high threshold (HT), based on their responses to nonnoxious mechanical stimuli, pinching, and noxious heat. The pruritogens activated two nonoverlapping STT neuron populations of recorded cells. Histamine and cowhage activated WDR and HT neurons, but all neurons activated by either one also responded to the noxious chemical compound capsaicin. The data indicate two independent itch pathways, both of which also convey pain sensation.



4. Sleep Apnea and Hypoxic Neuronal Loss in Mice

Yan Zhu, Polina Fenik, Guanxia Zhan, Emilio Mazza, Max Kelz, Gary Aston- Jones, and Sigrid C. Veasey



One of every 100 readers of this paragraph likely has sleep apnea. The immediate concern with sleep apnea is daytime sleepiness because of frequent nighttime sleep disruption. However, some studies have suggested that the resulting cycles of hypoxia and reoxygenation may cause longlasting neuronal damage. This week, Zhu et al. tested this idea in rodents. The authors exposed adult male mice to longterm intermittent hypoxia (LTIH) for 8 weeks. This treatment consisted of O2 reduction from 21 to 10% for 5 s every 90 s, which caused desaturation of oxyhemoglobin, not unlike obstructive sleep apnea. Six months later, wakefulness was irreversibly impaired compared with control mice. There was also impaired activation of the immediate early gene c-fos upon waking in dopamine neurons in the periaqueductal gray and noradrenergic neurons in the locus ceruleus. Among wakeactive neurons, only catecholamine neurons were diminished by LTIH. The NADPH oxidase inhibitor apocynin prevented the loss.






Source: Sara Harris


Society for Neuroscience



View drug information on Estradiol.

The Unexpected Connection Of Two Gene Regulation Mechanisms Points To New Ways For The Fight Against Leukemia

When the activity of individual genes it is longer required, there are two main mechanisms responsible for the "switching off", mainly DNA methylation and the Polycomb protein complex. Sometimes, these mechanisms lose their efficiency and some of the genes that should be "switched off" remain active. This, in turn, could lead to uncontrolled cellular proliferation, and tumorigenesis. These mechanisms, present both in lower organisms as well as in mammals, have always been thought to be separated and independent.


The work, which appears on the cover this week in the June issue of the prestigious journal Cancer Cell, carried out by researchers of the Differentiation and Cancer Programme, at the Centre for Genomic Regulation (CRG), in Barcelona (Spain), demonstrates the cross-talk between these two gene silencing mechanisms in patients suffering from acute leukemia. The work, led by the ICREA researcher Luciano Di Croce, head of the group Epigenetics and Cancer, at the CRG, performed in collaboration with Kristian Helin's group, at the Biotech Research and Innovation Centre in Copenhagen (Denmark), and Dr. Nomdedeu's group, at the Santa Creu and Sant Pau Hospital, in Barcelona, will have important consequences in the development of new anti-tumor therapies. On the one hand, the study shows a better understanding of the basic mechanisms of gene regulation and, on the other hand, identifies a possible new pathway to reactivate erroneously "switched off" genes in tumors. In 2002, in a study published in Science, Di Croce showed that uncontrolled DNA methylation contributed to tumor progression in its first stages. Less than a year ago, Di Croce's group described, in another study published in Nature, the biochemical connection between the Polycomb protein complex and the enzymes methylating the DNA (DNA methyltransferases).


In this new study, Di Croce has shown that the two mechanisms are not only interconnected in leukemic cells, but also that one reinforces the other and, more importantly, that one needs the other. Therefore - and this is one of the most interesting aspects of the investigation - if one of these mechanisms is blocked by specific drugs, the other will also be affected. The results achieved will allow, in the future, identifying new chemical compounds able to block both mechanisms simultaneously and exclusively, without altering other cellular mechanisms. For these reasons, this is one of the new investigations lines recently adopted by the group led by Di Croce.


CENTRE FOR GENOMIC REGULATION

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Barcelona Biomedical Research Park Building

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Appetite Decreased And Weight Loss Promoted By Blocking Brain Enzyme

Imagine being able to tone down appetite and promote weight loss, while improving the body's ability to handle blood sugar levels.



That's just what Tony Means, PhD, and his team at the Duke University Medical Center were able to do when they blocked a brain enzyme, CaMKK2, in mice.



"We believe we have identified an important drug development target that could potentially turn into a metabolic triple play: appetite control, weight loss and blood sugar management," said Means, who is the Nanaline H. Duke Professor and Chairman of Pharmacology and Cancer Biology.



For many years, scientists have been identifying and testing every step of the appetite stimulation and suppression pathways in search of a target. Such research is considered critical to finding ways for people to better control their weight and minimize their risk of developing diabetes, heart disease and other health conditions.



Activation of the enzyme CaMKK2 is just one step in the appetite stimulation pathway located in the hypothalamus section of the brain. An empty stomach releases the hormone ghrelin, which launches a cascade of signals that ultimately results in increased appetite.



Means and colleagues believed that CaMKK2 in the ghrelin pathway might be a likely candidate for study, because it activates AMPK, an enzyme that stimulates animals to eat and gain weight. They tested their theory in several ways, the results of which are published in the May issue of Cell Metabolism. The work was funded by NIH grants, as well as by the Australian Research Council, National Heart Foundation, and the National Health and Medical Research Council of Australia.



First they blocked CaMKK2 in mice with a specialized molecule inhibitor and then measured food intake. These mice ate significantly less food than untreated mice during the six days in which they were evaluated, and also lost body weight, which led the scientists to think they might be on to something.



Next they studied a group of mice that normally do not make CaMKK2 and found that the molecule inhibitor did not change feeding behavior or reduce weight. "The fact that blocking CaMKK2 worked in normal mice to make them eat less and lose weight, but not in mice missing the enzyme, provides compelling evidence that CaMKK2 signaling is a requirement for appetite control," Means said.



They also studied both normal mice and mice missing CaMKK2 to learn how these types responded to low-fat and high-fat diets. After nearly 30 weeks on the specific diets, the normal mice on the high-fat diet became diabetic - they were unable to respond to insulin and weren't able to manage blood sugar levels well. In contrast, the normal mice on a low-fat diet stayed healthy.



In mice missing CaMKK2, the scientists found that they stayed healthy regardless of whether they were on a low-fat or high-fat diet. The CAMKK2-negative mice apparently were protected from changes that lead to diabetes in a high-fat diet.



"Remarkably, we find that blocking CaMKK2 in the brain prevents the deposits of fat in liver and skeletal muscle that are characteristic of obese, diabetic patients," Means said. "We find this very exciting and are trying to understand the mechanism responsible for this protective effect, as well as to identify more potent drugs to inhibit CaMKK2."







Other contributing authors include Kristin Anderson, Thomas Ribar, Fumin Lin, Pamela Noeldner and Michelle Green of the Duke Department of Pharmacology and Cancer Biology; Michael Muehlbauer of the Sarah Steadman Center for Nutrition and Metabolism in the Duke University Medical School; Lee Witters of the Departments of Medicine and Biochemistry at Dartmouth Medical School and the Dartmouth Department of Biological Sciences; and Bruce Kemp of the St. Vincents Institute of Medical Research, the CSIRO Molecular and Health Technologies (a branch of Australia's national science agency) and the University of Melbourne in Australia.



Source: Mary Jane Gore


Duke University Medical Center

The Mechanism Of Sex Ratio Adjustment In A Pollinating Fig Wasp

Fig wasps are a model system for the study of sex ratio evolution because as more females enter a fig to lay their eggs they produce a higher proportion of sons.

How they achieve this has not confirmed before. We managed to poison females at varying times after entry into figs, without killing their offspring.

They produced most of their sons in the first few minutes and mostly daughters after that.

This simple mechanism leads to sex ratio adjustment because as more females enter a fig there is more competition for oviposition sites, and smaller clutches are less female-biased.


Dr. Steve Compton, University of Leeds, UK


Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.

Link to the journal


The Royal Society

Scientific Holiday Celebrates Evolution In Action

On February 12, groups worldwide will celebrate the birthday of Charles Darwin, the scientist who documented evolution through natural selection nearly 150 years ago. Today, Darwin's groundbreaking work on the origin of species forms the basis of modern evolutionary biology and is at the heart of biomedical research.


Evolution happens every day, and it affects every species including us. In fact, it's the source of a topic in the daily news: antibiotic resistance. Some bacteria have an evolutionary edge over others and, as a result, flourish in the presence of antibiotics while antibiotic-sensitive bacteria perish.


The National Institute of General Medical Sciences, a component of the National Institutes of Health, supports a wide range of basic research in evolutionary biology. A few recent findings are described below.


Got Milk?


If you're lactose intolerant, you're not alone most of the world's adults can't digest this sugar found in milk. African tribal people who took up cattle herding thousands of years ago are an interesting exception. Sarah Tishkoff of the University of Maryland discovered that natural selection for lactose tolerance was so strong that it evolved independently in three distinct rural African populations. Lactose tolerance enabled people to drink cow's milk during droughts and survive to produce more offspring who also carried the trait.


Staying Ahead of HIV


The HIV virus evolves very quickly, changing its genes to outwit medicines and the immune system. Making matters worse, people infected with HIV often carry many types of the virus each one possibly resistant against a different drug. Feng Gao of Duke University developed a test that finds drug-resistant HIV in the blood before treatment fails, potentially enabling doctors to intervene more quickly.


Say It Again, Gene


Don't be alarmed, but our genome is a cluttered mess thanks in large part to evolutionary processes that allow DNA sequences to repeat themselves. Evan Eichler of the University of Washington in Seattle wanted to find order in the genomic jumble. He used a form of calculus to develop a framework for reconstructing the evolutionary history of human genome reorganizations. By tracing the path of gene copying over time, the work offers a new window into understanding how diseases develop.


The Shape of Proteins Past


Joseph Thornton of the University of Oregon used computational and biochemical methods to resurrect a protein hundreds of millions of years old and determine its atomic structure, revealing in unprecedented detail the evolution of the molecule's structure and function. This is the first time researchers have reproduced an ancestral protein and determined its atomic structure, essentially traveling 450 million years in time to observe evolution in action.


NIH, National Institute of General Medical Sciences (NIGMS)

45 Center Dr. MSC 6200

Bethesda, MD 20892-6200

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Why Don't More Animals Change Their Sex?

Most animals, like humans, have separate sexes - they are born, live out their lives and reproduce as one sex or the other. However, some animals live as one sex in part of their lifetime and then switch to the other sex, a phenomenon called sequential hermaphroditism. What remains a puzzle, according to Yale scientists, is why the phenomenon is so rare, since their analysis shows the biological "costs" of changing sexes rarely outweigh the advantages.



A report by Yale scientists in the March issue of The American Naturalist says that while this process is evolutionarily favored, its rarity cannot be explained by an analysis of the biological costs vs benefits.



Sequential hermaphroditism naturally occurs in various organisms from plants to fishes. Following four decades of research that established why sex change is advantageous, the question remained why it is rare among animals. In this study, Yale graduate student Erem KazancД±oДџlu and his advisor Suzanne Alonzo, assistant professor of ecology and evolutionary biology, demonstrate that sex change is surprisingly robust against costs.



While the adaptive advantage of sex change is well understood, it is not clear why relatively few animals change sex. According to Alonzo, "An intuitive, yet rarely studied, explanation is that the considerable time or energy it takes to change sex make hermaphroditism unfeasible for most animals."



To test whether the biological costs of changing sex affect sex change actually occurs, the researchers built theoretical models of the hermaphrodite and separate-sex life histories. In their "game" models, sex change "players" vary the age of their sex change, while the separate-sex strategy responds by altering the number of male and female offspring it produces.



"We were surprised to see that a hermaphrodite could spend 30 percent of its lifetime in the process of change sex, and still persist in a population," said KazancД±oДџlu. "This suggests that only huge costs can disfavor sex change."



So, why is sex change so rare? And, why does one species of fish reproduce strictly as separate sexes, while another very closely related species flexibly changes sex? A comparative study of hermaphroditic and separate-sex mating systems, which the authors are currently performing, may provide a clue, according to KazancД±oДџlu, "Reproductive behaviors such as parental care seem to disfavor sex change in some species. We are investigating whether general patterns like these may explain the rarity of hermaphroditism."



Yale University and the National Science Foundation funded the research.



Citation: The American Naturalist (March 2008)


Suzanne Alonzo

Ecology & evolutionary biology


YALE

Sentry Enzyme Blocks Two Paths To Parkinson's Disease

The degeneration of brain cells that occurs in Parkinson's disease may be caused by either externally provoked cell death or internally initiated suicide when the molecule that normally prevents these fatal alternatives is missing, according to studies in mouse models by investigators at St. Jude Children's Research Hospital.


Parkinson's disease is a disease in which nerve cells in part of the brain called the substantia nigra die, resulting in the loss of dopamine, a nerve-signaling molecule that helps control muscle movement. The absence of dopamine from these cells, called dopaminergic neurons, causes a loss of muscle control, trembling and lack of coordination.


The molecule that prevents damage to the substantia nigra is an enzyme called GST pi ("pie"). This molecule stands like a sentry at the crossroads of several biochemical pathways, any one of which can lead to Parkinson's disease, the researchers reported in an article in the Feb. 1 early online edition of Proceedings of the National Academy of Sciences.


The job of the antioxidant GST pi is to protect the cell from death caused by either environmental toxins (externally evoked cell death), such as herbicides and pesticides, or a self-destruction process called apoptosis (cell suicide), triggered by certain stressful conditions in the cell. If GST pi levels are reduced or this enzyme is overwhelmed by toxins, these nerves are at increased risk of death. Previous research has shown that the ability of GST pi to protect cells against toxic molecules is directly linked to the ability of cancer cells with excessive amounts of this enzyme to reduce the effectiveness of chemotherapy.


The finding that GST pi plays a key role in preventing Parkinson's disease suggests that measuring levels of this enzyme might be an effective way to determine individuals at risk for developing this disease, according to Richard Smeyne, Ph.D., an associate member of the Department of Developmental Neurobiology at St. Jude. "In the future, treatments that increase GST pi levels in the substantia nigra might help to prevent or delay the onset of Parkinson's disease or reduce its severity," said Smeyne, the report's senior author.


GST pi is one of a family of similar enzymes that eliminate free radicals generated by pesticides and other chemicals. Two members of this family are present in the brain, but only one of them, GST pi, is found in the dopaminergic neurons of the substantia nigra. Free radicals are highly unstable molecules that readily interact with other molecules, causing cell damage.


The study sheds light on the cause of most cases of Parkinson's disease, which currently are unexplained. "The majority of these cases of Parkinson's disease appear to arise because individuals who have a genetic susceptibility to the disease are exposed to environmental toxins such as pesticides and herbicides, which trigger the formation of free radicals that kill dopaminergic neurons in the substantia nigra," Smeyne said. "We also know that GST pi blocks the process of cell suicide triggered by stresses that the cell can't overcome, such as an increase in the presence of free radicals or a loss of the cell's ability to produce energy."















Smeyne's team showed that of the two known types of GST in the brain, only GST pi was present in the dopaminergic neurons that are lost in Parkinson's disease. The scientists then treated two different populations of mice with MPTP, a chemical that causes loss of these cells, in order to determine if levels of GST pi changed. In mice known to be sensitive to MPTP, there was a complete but transient loss of GST pi in the dopaminergic neurons of the substantia nigra, while the same area of the brain in MPTP-resistant mice never completely lost GST pi and recovered their original levels within 12 hours.


In addition, the team showed that when MPTP-resistant mice were treated with this drug, the presence of GST pi in the dopaminergic neurons prevented activation of cJUN, a molecule that triggers apoptosis. These findings are evidence that GST pi prevents apoptosis in dopaminergic neurons of the substantia nigra, Smeyne said.


The investigators also showed in cell culture studies that blocking production of GST pi in substantia nigra cells left them vulnerable to MPTP, causing a significant death rate among these cells. In addition, when the investigators blocked GST pi production in the dopaminergic neurons of the substantia nigra, about one-quarter of them died, even though they were not treated with MPTP. "This suggests that even in the absence of MPTP the enzyme GST pi plays a critical role in preventing cell death that may occur with the natural buildup of free radicals," Smeyne said.


Finally, the investigators studied the effect of MPTP on the substantia nigra of normal, "wild-type" mice and mice that lacked one (+/-) or both (-/-) genes for GST pi. Wild-type and GST pi (+/-) mice showed similar resistance to MPTP, but GST pi (-/-) mice lost slightly less than half of their dopaminergic neurons following treatment with MPTP. Six hours after MPTP treatment, the formation of free radicals increased 300 percent in the substantia nigra of GST pi (-/-) mice compared with the substantia nigra of GST pi (+/+) mice. These results are additional evidence that GST pi may play an important role in preventing Parkinson's disease," Smeyne said.


Results of the St. Jude study showing the importance of GST pi could help to explain previous work by other researchers linking loss of this enzyme to destruction of dopaminergic neurons. For example, there is some evidence that alterations in the gene for GSP pi are linked to increased risk of Parkinson's disease after pesticide exposure. Also, although most Parkinson's disease cases have no known cause, experts believe that they are caused by the interaction of genetic susceptibility to Parkinson's disease with exposure to a variety of environmental factors, such as pesticides and herbicides.


"Therefore, the new findings bring researchers a step closer to understanding why Parkinson's disease occurs and potentially how to develop more effective treatments for it," Smeyne said.


Other authors of this study include St. Jude researchers Michelle Smeyne, Justin Boyd and Kennie Raviie Shepherd, who did most of the work; Yun Jiao, Brooks Barnes Pond and Matthew Hatler (St. Jude); and Roland Wolf and Colin Henderson (Ninewells Hospital and Medical School, Dundee, UK).


The work was supported in part by the National Institutes of Health and ALSAC.


St. Jude Children's Research Hospital


St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit stjude.


St. Jude Children's Research Hospital

332 N. Lauderdale St., Mail Stop 761

Memphis, TN 38122

United States

stjude

Mythical Monster Hydra In The Petri Dish - Jellyfish With Several Heads Discovered

In a story from Greek mythology, Hercules defeats the many-headed Hydra living in water. The story appears magical -
monsters with several heads do not exist. Scientists from the Animal Ecology and Cell Biology Institute of the University of Veterinary Medicine
Hannover were able to prove the that this is not the case; they discovered many-headed jellyfish, which develop when certain developmental genes are
deactivated.



In a study published in the August 1 issue of the online, open-access journal PLoS ONE, the scientists developed a novel method for marine animals to
block the so-called Cnox genes in living cnidarians. These genes are closely related to the Hox genes of the "higher" animals and are responsible
for forming the body along the main body axis, from the anterior to the posterior.



Multiple-headed animals were until now merely recognised as a rare developmental anomaly of unknown origin in various animals. Now for the first time,
having many heads is shown to be an inducible and reproducible development when a single regulatory gene is experimentally deactivated.



In the laboratory, the mythical Hydra has become a reality and provides new insights into the genetic regulation of head formation in basal animals.
If a certain Cnox gene is deactivated, scientists can generate jellyfish of the Eleutheria dichotoma species with precisely two heads, whereby both
heads are completely functional (regarding food intake, for instance). Deactivation of another gene leads to multiple heads.



In nature, jellyfish (or other animals) with multiple heads are rarely found. This may be because adding heads on an otherwise unaltered body appears
to offer no fitness advantages on which natural selection could act. The TiHo researchers Dr. Wolfgang Jakob and Prof. Dr. Bernd Schierwater report,
however, that the structural changes they see in association with polycephaly could have conveyed substantial advantages to drive macro-evolutionary
change.


"It would be conceivable that colony-forming cnidarians, including those which build coral reefs, have emanated from individually living ancestors.
Parallel to the generation of multiple heads the animals might have enlarged and structured their posterior body region in such a way that animal
colonies were able to emerge," Schierwater reported. Background to such thoughts is that cnidarian colonies are made up of multiple heads which
share a common "gut" (gastrovascular) system.



A significant difference between the many-headed jellyfish in the laboratory and the many-headed mythical monster Hydra is worth mentioning. Every
time Hercules decapitated the Hydra, two new heads immediately grew back. In the case of the Eleutheria jellyfish in the laboratory, only one head
regrows after decapitation.



Jakob W, Schierwater B (2007)

Changing Hydrozoan Bauplans by Silencing Hox-Like Genes

PLoS ONE 2(8): e694. doi:10.1371/journal.pone.0000694

plosone/doi/pone.0000694




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USA

Rett Syndrome Discovery Advances Understanding Of Neurological Missteps

In 1999, when Dr. Huda Zoghbi and her Baylor College of Medicine colleagues identified a mutation of the gene MeCP2 as the culprit in Rett syndrome, a neurodevelopmental disorder, the discovery was only the prelude to understanding a symphony of neurological missteps.



Unraveling the story of MeCP2 demonstrates the finicky nature of neurons that work best when the recipe for the proteins affecting them is followed exactly. Zoghbi and her collaborators describe the role MeCP2 plays in the brain in a report that appears in the current issue of the journal Science.



"Whether you lose the protein or gain too much, the symptoms in the brain overlap quite a bit," said Zoghbi, who is a BCM professor of pediatrics, neurology, neuroscience, molecular and human genetics and a Howard Hughes Medical Institute investigator. "The brain is very sensitive to its physiological equilibrium."



Yet the brain or neurons in it can demonstrate a problem with only a limited range of symptoms - autism, seizures or mental retardation.



"The symptoms are those of an unhappy neuron," said Zoghbi. Yet as the MeCP2 studies show, these symptoms can have different causes. That fact may mean that what outwardly appears to be the same disease could have very different beginnings and require wholly different treatments.



Zoghbi and her colleagues found that MeCP2 is a key regulator that can turn on and off genes that govern activities in the neurons of the hypothalamus. While MeCP2 can turn off a gene, it is more likely to turn it on.



As infants, girls with Rett syndrome seem normal for at least six months. Between the ages of 6 and 18 months, however, their development stops and they begin to regress, losing the ability to talk. Then they begin to have problems walking and keeping their balance and develop typical hand-wringing behavior. Many of their symptoms mirror those of autism. Zoghbi's laboratory was the first to identify a mutation in the MeCP2 gene that results in too little of this protein, causing girls to develop Rett. Boys who suffer from a disorder linked to an excess of MeCP2 have impaired motor function, seizures and mental retardation with autism-like behavior.



In trying to find out how the alterations in MeCP2 affect the brain, the scientists began their studies in the hypothalamus because symptoms of Rett syndrome such as anxiety, sleep disturbance and slowed growth can all be attributed to problems in that part of the brain. Previous studies of the whole brain proved inconclusive, and by targeting a very specific area of the brain, Zoghbi and her collaborators hoped to zero in on the problem.



"Loss of function of the MeCP2 gene causes Rett syndrome," said Maria Chahrour, a BCM graduate student and first author of the report. Doubling or tripling MeCP2 levels causes other neurological disorders. To better understand the protein, the scientists decided to study mice that either lacked MeCP2 or had too much of it.
















They dissected the hypothalamus in both kinds of mice and looked at changes in the genes compared to the same genes in normal mice.



"There are thousands of genes changed by MeCP2," said Chahrour. In both the mice who had no MeCP2 and those who had too much of the dysfunctional gene, they found changes in expression of thousands of genes. Surprisingly, they found that in at least 85 percent of the genes, MeCP2 turned the gene on. In fact, they found that it associates with CREB1, another gene tasked with turning on genes.



Interestingly, although the two diseases share many features, having no protein versus having too much caused opposite effects on gene expression, suggesting again that "the symptoms are those of an unhappy neuron," said Zoghbi. Yet as the MeCP2 studies show, these symptoms can have different causes. That fact may mean that what outwardly appears to be the same disease could have very different beginnings and require wholly different treatments.



"Because MeCP2 regulates thousands of genes, it does not make sense to target each of them individually in designing treatments," Chahrour said. "We are going to have to find a therapeutic strategy that can bypass MeCP2 and restore the normal order in the brain," she said.







Others who took part in this work include Sung Yun Jung, Chad Shaw and Jun Qin of BCM and Xiaobo Zhou and Stephen T. C. Wong of The Methodist Hospital Research Institute and Weill Cornell College of Medicine.



Funding for this work comes from the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, the National Institute of Child Health and Human Development Mental Retardation and Developmental Disabilities Research Center, the International Rett Syndrome Foundation and the Simons Foundation.



Full article available at sciencemag/



Source: Graciela Gutierrez


Baylor College of Medicine

Human Genomics In China

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 coordinately 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. His efforts were supported by the academician LIANG Dong-Cai, Deputy Director of the NSFC Committee and of the Department of Life Sciences, 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 leukemia, solid tumors (including liver cancer, colorectal cancer and nasopharyngeal cancer) and genetic diseases (such as deaf). 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 center 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 center was officially inaugurated as the Chinese National Human Genome Center at Shanghai (abbreviated as the South Center), thus becoming the first national research center located in the Zhangjiang Hi-Tech Park of Pudong District. The academician CHEN Zhu has served as the director of the center ever since, while ZHAO Guo-Ping acted as the executive director of the center 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 centers. 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 de- termined 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 centers 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. Coordinately, 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 (pathologens 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 (biodb.sgst.cn) . 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 centers, China adopted the international model initially - organizing grand scientific program/projects and establishing genome centers 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 centers 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 centers. 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 center was tempered, and the abilities of the team members were improved. Meanwhile, influenced by the center, an array of "omics" and systems biomedicine research centers were gradually set up in the Zhangjiang HiTech Park of Shanghai. Collaborating with these research centers, the South Center has been accomplishing its transformation from a platform technology center focusing on sequencing and genotyping services to a research center 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 center continues to promote the formation and transformation of intellectual property based on the biomedicine research achievements.



As a matter of fact, within the past ten years, the progress of genomics in China was a sort of frogleap development in terms of scale, quality, interdisciplinarity, 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 "culture 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), whereas 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. That should be one of the reasons why 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 frogleap 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, leukemia pathogenesis and so on, 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 interdisciplinarity 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 О» phage cos 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." To be honest, 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 frogleap". Some of the minireviews 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



doi: 10.1007/s11427-009-0016-5 MOST-Shanghai Key Laboratory of Disease and Health Genomics

The Chinese National Human Genome Center at Shanghai

The People's Republic of China



Sci China Ser C-Life Sci | Jan. 2008 | vol. 52 | no. 1 | 2-6

scichina:8082/sciC/CN/volumn/current.shtml



Source: Li Jiyuan


Science in China Press