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JCVI Scientists Publish First Bacterial Genome Transplantation Changing One Species to Another   ----Research is important step in further advancing field of Synthetic Genomics----   ROCKVILLE, MD — June 28, 2007 — Researchers at the J. Craig Venter Institute (JCVI) announced the results of work on genome transplantation methods allowing them to transform one type of bacteria into another type dictated by the transplanted chromosome. The work, published online in the journal Science, by JCVI’s Carole Lartigue, Ph.D. and colleagues, outlines the methods and techniques used to change one bacterial species, Mycoplasma capricolum into another, Mycoplasma mycoides Large Colony (LC), by replacing one organism’s genome with the other one’s genome. “The successful completion of this research is important because it is one of the key proof of principles in synthetic genomics that will allow us to realize the ultimate goal of creating a synthetic organism,” said J. Craig Venter, Ph.D., president and chairman, JCVI. “We are committed to this research as we believe that synthetic genomics holds great promise in helping to solve issues like climate change and in developing new sources of energy.”   Methods and techniques The JCVI team devised several key steps to enable the genome transplantation. First, an antibiotic selectable marker gene was added to the M. mycoides LC chromosome to allow for selection of living cells containing the transplanted chromosome. Then the team purified the DNA or chromosome from M. mycoides LC so that it was free from proteins (called naked DNA). This M. mycoides LC chromosome was then transplanted into the M. capricolum cells. After several rounds of cell division, the recipient M. capricolum chromosome disappeared having been replaced by the donor M. mycoides LC chromosome, and the M. capricolum cells took on all the phenotypic characteristics of M. mycoides LC cells.   As a test of the success of the genome transplantation, the team used two methods — 2D gel electrophoresis and protein sequencing, to prove that all the expressed proteins were now the ones coded for by the M. mycoides LC chromosome. Two sets of antibodies that bound specifically to cell surface proteins from each cell were reacted with transplant cells, to demonstrate that the membrane proteins switch to those dictated by the transplanted chromosome not the recipient cell chromosome. The new, transformed organisms show up as bright blue colonies in images of blots probed with M. mycoides LC specific antibody.   The group chose to work with these species of mycoplasmas for several reasons — the small genomes of these organisms which make them easier to work with, their lack of cell walls, and the team’s experience and expertise with mycoplasmas. The mycoplasmas used in the transplantation experiment are also relatively fast growing, allowing the team to ascertain success of the transplantation sooner than with other species of mycoplasmas.   According to Dr. Lartigue, “While we are excited by the results of our research, we are continuing to perfect and refine our techniques and methods as we move to the next phases and prepare to develop a fully synthetic chromosome.” Genome transplantation is an essential enabling step in the field of synthetic genomics as it is a key mechanism by which chemically synthesized chromosomes can be activated into viable living cells. The ability to transfer the naked DNA isolated from one species into a second microbial species paves the way for next experiments to transplant a fully synthetic bacterial chromosome into a living organism and if successful, “boot up” the new entity. There are many important applications of synthetic genomics research including development of new energy sources and as means to produce pharmaceuticals, chemicals or textiles.   This research was funded by Synthetic Genomics Inc.     Background and Ethical Considerations The work described by Lartigue et al. has its genesis in research begun by Dr. Venter and colleagues in the mid-1990’s after sequencing Mycoplasma genitalium and beginning work on the minimal genome project. This area of research, trying to understand the minimal genetic components necessary to sustain life, underwent significant ethical review by a panel of experts at the University of Pennsylvania (Cho et al, Science December 1999:Vol. 286. no. 5447, pp. 2087 – 2090). The bioethical group's independent deliberations, published at the same time as the scientific minimal genome research, resulted in a unanimous decision that there were no strong ethical reasons why the work should not continue as long as the scientists involved continued to engage public discussion. In 2003 Drs. Venter, Smith and Hutchison made the first significant strides in the development of a synthetic genome by their work in assembling the 5,386 base pair bacteriophage φX174 (phi X). They did so using short, single strands of synthetically produced, commercially available DNA (known as oligonucleotides) and using an adaptation of polymerase chain reaction (PCR), known as polymerase cycle assembly (PCA), to build the phi X genome. The team produced the synthetic phi X in just 14 days. Dr. Venter and the team at JCVI continue to be concerned with the societal implications of their work and the field of synthetic genomics generally. As such, the Institute’s policy team, along with the Center for Strategic & International Studies (CSIS), and the Massachusetts Institute of Technology (MIT), were funded by a grant from the Alfred P. Sloan Foundation for a 15-month study to explore the risks and benefits of this emerging technology, as well as possible safeguards to prevent abuse, including bioterrorism. After several workshops and public sessions the group is set to publish a report in summer 2007 outlining options for the field and its researchers.     About the J. Craig Venter Institute The J. Craig Venter Institute is a not-for-profit research institute dedicated to the advancement of the science of genomics; the understanding of its implications for society; and communication of those results to the scientific community, the public, and policymakers. Founded by J. Craig Venter, Ph.D., the JCVI is home to approximately 500 scientists and staff with expertise in human and evolutionary biology, genetics, bioinformatics/informatics, information technology, high-throughput DNA sequencing, genomic and environmental policy research, and public education in science and science policy. The legacy organizations of the JCVI are: The Institute for Genomic Research (TIGR), The Center for the Advancement of Genomics (TCAG), the Institute for Biological Energy Alternatives (IBEA), the Joint Technology Center (JTC), and the J. Craig Venter Science Foundation. The JCVI is a 501 (c)(3) organization. For additional information, please visit http://www.JCVI.org.

The Voyage of  the Sorcerer II Global Ocean Sampling (GOS) Expedition   Learn more about the voyage and details of the Sorcerer II’s expedition at this interactive link:  http://www.sorcerer2expedition.org/version1/HTML/main.htm More than Six Million New Genes, Thousands of New Protein Families, and Incredible Degree of Microbial Diversity Discovered from First Phase of Sorcerer II Global Ocean Sampling Expedition   Unprecedented amount of data deposited in CAMERA database; features enhanced tools to visualize and analyze metagenomic data   ROCKVILLE, MD—March 13, 2007— Researchers from the J. Craig Venter Institute (JCVI) announced the publication of several studies from the Sorcerer II Global Ocean Sampling Expedition (GOS) in PLoS Biology (www.plosbiology.org) detailing the discovery of millions of new genes, thousands of new protein families and specifically the characterization of thousands of new protein kinases from ocean microbes using whole environment shotgun sequencing and new computational tools. Researchers believe these data will lead to better understanding of key biological processes which could eventually offer new ideas for alternative energy production and could offer solutions to deal with climate change and other environmental issues. The GOS dataset is 90-fold larger than other marine metagenomic datasets, thus making it the largest ever released in the public domain. The GOS analysis also nearly doubles the number of previously known proteins. This enormous amount of data allowed the researchers to better understand the genomic structure and evolution of microorganisms, as well as the function of important protein families such as protein kinases, which are key regulators of cellular function in all organisms. Although invisible to the naked eye, microbes make up the vast majority of life on the planet and are responsible for creation and maintenance of Earth’s atmosphere, it is important to understand the role and function of these organisms to ensure the survival of the planet and human life on it. “This publication is not only providing an unprecedented level of new genes and protein family discoveries, but is also pivotal in that we have provided compelling analysis of evolution and function of these genes and proteins within the larger context of organisms interacting with their environment,” said J. Craig Venter, Ph.D., founder and chairman, the J. Craig Venter Institute. “Given the findings, it’s clear that we’ve only begun to scratch the surface of understanding the microbial world around us.” The Sorcerer II Expedition began with a pilot project in 2003 in the Sargasso Sea near Bermuda in which more than one million new genes and hundreds of new photoreceptors were discovered in what was thought to be an area of low diversity. The GOS publication today is a result of ocean water sampling conducted from Halifax, Nova Scotia to the Eastern Tropical Pacific during the two year circumnavigation by the Sorcerer II Expedition. The Gordon and Betty Moore Foundation and the United States Department of Energy, Office of Science, funded the sequencing and analysis of the Expedition. The JCVI funded the operation of the vessel. The group also announced today the launch of a new online database and high-speed computational resource, Community Cyberinfrastructure for Advanced Marine Microbial Ecology Research and Analysis (CAMERA). Funded by a grant from the Moore Foundation of $24.5 million over seven years, CAMERA was developed by the UC San Diego Division of the California Institute for Telecommunications and Information Technology (Calit2) in partnership with JCVI and UCSD’s Center for Earth Observations and Applications (CEOA) at Scripps Institution of Oceanography. "The scale and complexity of the GOS data required Calit2 to architect a powerful new cyberinfrastructure to enable both interactive access as well as high performance computation on the data by the global metagenomic community, " said Larry Smarr, Calit2 director and principal investigator on CAMERA. CAMERA houses metagenomic data and provides the advanced software tools and computer hardware to analyze these data. Using dedicated optical circuits, CAMERA permits scientists to connect their local laboratory computers directly to the CAMERA database and tools using the National LambdaRail or international optical circuits, resulting in up to a hundred-fold increase in bandwidth over current standards. CAMERA has been in beta testing since January 2007 and today is available to researchers worldwide. In addition to the CAMERA database, the GOS data is also being deposited in the U.S. National Institutes of Health’s public database, GenBank. The GOS publication was a result of intensive analysis of these data by scientists from the JCVI along with collaborators at four University of California campuses (San Diego, Los Angeles, Berkeley and Davis), University of Southern California, Salk Institute for Biological Studies, Burnham Institute, University of Hawaii, Brown University, Universidad Nacional Autonoma de Mexico, Universidad de Costa Rica, Universidad de Concepcion, Bedford Institute of Oceanography, Smithsonian Tropical Research Institute, and Rutgers University.   PLoS Biology Publications: The Global Ocean Sampling (GOS) Expedition The Sorcerer II Global Ocean Sampling Expedition: Northwest Atlantic through Eastern Pacific Rusch et al. describe the results of metagenomic analysis of 37 samples taken aboard Sorcerer II during its voyage between Halifax, Nova Scotia and French Polynesia in 2003 to 2004, combined with seven samples collected during the pilot study in the Sargasso Sea. To capture the DNA, scientists onboard the Sorcerer II collected water every 200 nautical miles and then filtered it through progressively smaller filters to collect bacteria and then viruses. The DNA extracted for these publications were from the filter that collects mostly bacteria. The group analyzed a massive dataset consisting of 7.7 million DNA sequences totaling 6.3 billion base pairs. Following from the Sargasso Sea pilot study, they continued to find a great degree of diversity both within and across the sampling sites. Researchers identified 60 highly abundant ribotypes (roughly equivalent to species) however, the inter-species variation and the variation of organisms within the same environment suggests that while the microbes might be similar at an rRNA level they can differ greatly at a biochemical and genomic level. While variation is known to be closely linked to environment, this all encompassing genetic survey has identified new and unexpected links between variation and the environment. For example, the class of proteins known as proteorhodopsins absorbs either blue or green light. This study revealed that the blue and green variants are found in different environments with blue light preferred in the open ocean and green light preferred in coastal environments. Identifying these associations should greatly enhance our understanding of marine systems and the environmental factors upon which they depend. To handle the enormous volume of data generated from this phase of the Expedition, the team developed new computational methods to assemble and analyze these data. One comparative genomic method termed “fragment recruitment,” allowed researchers to look at genome structure, microbial evolution, and diversity on many levels. Another, “extreme assembly”, as the name implies, enabled researchers to assemble very large segments of DNA from the abundant but previously hard to analyze genomes of organisms. Finally, they developed a tool to assess the similarity between whole metagenome databases. According to lead author Doug Rusch, Ph.D., computational scientist at the JCVI, “We know so little about the organisms in our environment mostly because we have lacked the genomic and computational tools for understanding and examining these organisms. We believe that this publication and the new tools we developed will help to unleash a new era of enhanced knowledge of the biological processes of microbial communities and this new understanding will begin to unlock the mysteries of unseen life.”   The Sorcerer II Global Ocean Sampling Expedition: Expanding the Universe of Protein Families Characterization of microbial communities has been limited in the past by the difficulty in culturing organisms in the laboratory. With whole environment shotgun sequencing techniques, environments such as ocean microbial communities can now be better understood at the DNA and protein level. Yooseph et al. report on the 6.12 million new proteins uncovered from 7.7 million GOS sequences by using a novel sequence clustering approach. This nearly doubles the number of known proteins. The researchers found that the GOS dataset covered almost all of the known prokaryote (bacterial and archaeal) protein families and that there were 1,700 totally unique large protein families in the GOS dataset, not matching any known families. A surprising number of the new protein families discovered are in viruses. Researchers were also able to match 6,000 previously unmatched sequences in current protein databases to proteins found in the GOS dataset. Given the extraordinary rate of discovery of new proteins and protein families, the researchers conclude that there are likely many more protein families to be discovered both in microbes and viruses given the rate of discovery in this first phase of the GOS Expedition. The data also suggest that this is much more yet to be discovered about biological diversity of microbes. The team also found that several protein domains (the conserved structural units in proteins) that were previously thought to exist only in one of the four kingdoms of life (bacteria, archaea, eukaryotes, viruses) have GOS examples in another kingdom. These kingdom-crossing families may be proteins whose lineages are more ancient than previously assumed or they may have arisen due to lateral gene transfers. To assess the impact of the GOS data on known protein families, the team also investigated several protein families in detail. In addition to increasing substantially the size and diversity of these families, the GOS sequences increased the understanding of the evolution and function of these proteins. One example is those that repair DNA damage due to UV light (photolyases). While sunlight has benefits to the microbes, like with humans, sunlight also has the potential to be harmful to cells exposed to it. The team discovered many new proteins that protect these organisms from UV ray damage and some that are involved in repairing UV damage. These proteins were found in all organisms in the dataset, even in viruses. Another example is glutamine synthetase (GS), the protein that plays a key role in nitrogen metabolism. More than 9,000 GS or GS-like sequences were uncovered, with a large number of sequences of type II GS (one of the three GS types). This was unexpected because type II GS is associated more with eukaryotes, not bacteria and viruses, and not many eukaryotes are expected in the filters that were analyzed. The researchers theorize that this could be due to lateral gene transfer from eukaryotes, or more likely due to gene duplication before prokaryotes and eukaryotes diverged into two branches of life. Shibu Yooseph, Ph.D., lead author and computational scientist at JCVI said, “The analysis we have done so far with this publication shows a tremendous diversity of organisms at the protein level and going forward, I think we will continue to see this tremendous amount of diversity. These data open up a whole new set of research efforts from a computational perspective in designing better tools to be able to deal with this sort of data, as well as making observations on evolution and how functions evolved for these protein families”   Structural and Functional Diversity of the Microbial Kinome The availability of the GOS metagenomic data along with other large microbial genome data sets is enabling more research into specific kinds of protein families. Of particular interest to a wide variety of researchers are kinase families. Protein kinases are protein enzymes that regulate many of the most basic cellular functions in humans and other eukaryotes. They are key targets for cancer and other disease drug development. Previously, it was thought that different families of kinases were responsible for these types of cell regulation in prokaryotes (bacteria) versus eukaryotes (animals and other non-bacteria). Eukaryote protein kinases (ePK) were most common in eukaryotes, histidine kinases in bacteria. However, in their PloS Biology publication Kennan et al. show that with the scope and diversity of the GOS data that ePK-like kinases (ELKs) are indeed very prevalent in bacteria, in fact, more so than histidine kinases. This finding is even shedding some light on human kinases. The research team has shown that the ePK is just one family in a diverse superfamily of enzymes that all share a common protein kinase-like (PKL) fold (shape). Using sensitive profile methods, the researchers discovered more than 45,000 kinase sequences from the GOS and other public data sources and grouped these into 20 diverse families, of which ePKs were just one. The GOS data doubles the size of most PKL families and triples the number of known ePK-like kinases (ELK). Many of these families exhibited eukaryote-like structure and function of their proteins and thus the researchers conclude that several of these protein families existed before the divergence of the three domains of life. The authors concluded this work shows the power of metagenomic data in allowing better understanding of any gene family and has opened the door to further research into the mechanisms of protein families and their function, structure and evolution. About JCVI The J. Craig Venter Institute is a not-for-profit research institute which through its two operating divisions, The Institute for Genomic Research (TIGR) and The Center for the Advancement of Genomics (TCAG) advances the science of genomics; the understanding of its implications for society; and communication of those results to the scientific community, the public, and policymakers. Founded by J. Craig Venter, Ph.D., the JCVI is home to approximately 500 scientists and staff with expertise in human and evolutionary biology, genetics, bioinformatics/informatics, information technology, high-throughput DNA sequencing, genomic and environmental policy research, and public education in science and science policy. The JCVI is a 501 (c)(3) organization. For additional information, please visit www.jcvi.org Moore Foundation The Gordon and Betty Moore Foundation, established in September 2000, works in collaboration with grantees and other partners to achieve significant and measurable outcomes in three areas: environmental conservation, science and the San Francisco Bay Area. In April 2004, the Foundation launched its 10-year Marine Microbiology Initiative, with the goal of attaining new knowledge regarding the composition, function and ecological role of microbial communities in the world’s oceans. www.moore.org Calit2 The California Institute for Telecommunications and Information Technology, a partnership between UC San Diego and UC Irvine, houses over 1,000 researchers organized around more than 50 projects on the future of telecommunications and information technology and how these technologies will transform a range of applications important to the economy and citizens' quality of life. www.calit2.net US Department of Energy Office of Science DOE's Office of Science is the single largest supporter of basic research in the physical sciences in the nation, manages 10 world-class national laboratories, and builds and operates some of the nation's most advanced R&D user facilities.  Its website address is www.science.doe.gov.  DOE's Genomics:  GTL program aims to use the department's unique computational capabilities and research facilities to understand the activities of single-cell organisms on three levels:  the proteins and multi-molecular machines that perform most of the cell's work; the gene regulatory networks that control these processes; and microbial associations or communities in which groups of different microbes carry out fundamental functions in nature.  Once researchers understand how life functions at the microbial level, they hope to use the capabilities of these organisms to help meet many of our national challenges in energy and the environment.  The program will combine research in biology, engineering and computation with the development of novel facilities for high-throughput biology projects.  More information on the department's genomics programs is on the Web at www.doegenomes.org. PLoS Biology PLoS Biology is a peer-reviewed , open-access journal that features research articles of exceptional significance in all areas of biology. It is ranked in the top tier of life science journals by the Institute for Scientific Information (ISI) , with an impact factor of 14.7. Media Contacts JCVI: Heather E. Kowalski, 202-294-9206, hkowalski@kowalskicommunications.com Calit2: Doug Ramsey, 858-822-5825, dramsey@soe.ucsd.edu PLoS Biology: Natalie Bouaravong, 415-568-3445, nbouaravong@plos.org Source: JCVI Press Release # # #

FDA Clears Breast Cancer Specific Molecular Prognostic Test

Feb 6, 2007. The U.S. Food and Drug Administration (FDA) today cleared for marketing a test that determines the likelihood of breast cancer returning within five to 10 years after a woman's initial cancer. It is the first cleared molecular test that profiles genetic activity. The MammaPrint test uses the latest in molecular technology to predict whether existing cancer will metastasize (spread to other parts of a patient's body). The test relies on microarray analysis, a powerful tool for simultaneously studying the patterns of behavior of large numbers of genes in biological specimens. The recurrence of cancer is partly dependent on the activation and suppression of certain genes located in the tumor. Prognostic tests like the MammaPrint can measure the activity of these genes, and thus help physicians understand their patients' odds of the cancer spreading. MammaPrint was developed by Agendia, a laboratory located in Amsterdam, Netherlands, where the product has been on the market since 2005. "Clearance of the MammaPrint test marks a step forward in the initiative to bring molecular-based medicine into current practice," said Andrew C. von Eschenbach, M.D., Commissioner of Food and Drugs. "MammaPrint results will provide patients and physicians with more information about the prospects for the outcome of the disease. This information will support treatment decisions. Agendia compared the genetic profiles of a large number of women suffering from breast cancer and identified a set of 70 genes whose activity confers information about the likelihood of tumor recurrence. The MammaPrint test measures the level of activity of each of these genes in a sample of a woman's surgically removed breast cancer tumor, then uses a specific formula, known as an algorithm, to produce a score that determines whether the patient is deemed low risk or high risk for spread of the cancer to another site. The result may help a doctor in planning appropriate follow-up for a patient when used with other clinical information and laboratory tests. The MammaPrint is the first cleared in vitro diagnostic multivariate index assay (IVDMIA) device. Several months ago, FDA issued a draft guidance document concerning the need for these complex molecular tests to meet pre-market review and post-market device requirements even when the tests are developed and used by a single laboratory. Although FDA regulates diagnostic tests sold to laboratories, hospitals and physicians, it uses discretion when regulating tests developed and performed by single laboratories. On February 8, FDA will hold a public meeting to discuss its draft guidance document describing its regulatory approach to this type of test. "There have been rapid advances in microarrays and other pioneering diagnostics, and a corresponding increase in the use and impact of these complex tests. This has prompted FDA to take a closer look at the potential risks as well as the benefits associated with such tests when they are developed and used in laboratories," remarked Steven Gutman, M.D., Director, Office of In Vitro Diagnostic Device Evaluation. "This test clearance takes into account the development of these innovative technologies and ensures public health by carefully evaluating their performance." Prior to clearance, FDA requested evidence that the MammaPrint had been properly validated for its intended use. Agendia submitted data from a study using tumor samples and clinical data from 302 patients at five European centers. These studies confirmed that the test was useful in predicting time to distant metastasis in women who are under age 61 and in the two earliest stages of the disease (Stage I and Stage II) and who have tumor size equal to or less than five centimeters and no evidence that the cancer has spread to nearby lymph nodes (lymph node negative). FDA plans to publish a special controls guidance document within the next 60 days describing types of data that should support claims for genetic profiling for breast cancer prognosis. According to the American Cancer Society, an estimated 178,480 new cases of invasive breast cancer will be diagnosed among women in the United States this year and over 40,000 women are expected to die from the disease. Source: FDA Press Release

Cancer and Genomics - Real time qRT-PCR as a reliable tool for gene-expression analysis

By Dr. Kent Persson, Ph.D. and Dr. Neerja Sethi, Ph.D., Astragen LLC Human cancer is fundamentally a disease of the genome, resulting from accumulation of complex genetic changes in the genome, including chromosomal aberrations, inactivation of tumor suppressor genes, single nucleotide polymorphisms (SNPs), activation of cellular oncogenes or oncogenes introduced by exogenous infectious agents. Currently, there is an urgent need to develop technologies to accelerate the field of cancer genomics that have diagnostic and therapeutic applications in wide areas of cancer research. Each type of cancer has its characteristic aberrations in the genetic composition that result in alteration in gene expression levels. Since each cancer has its own molecular signature, the essential scientific goals are to develop high-throughput technologies that will allow us to catalog the genetic origins of malignancies for various cancers for improved detection, diagnosis and treatment. SNPs. The mapping of the human genome has revealed that the extent of genetic variation is much larger than previously estimated (1,2). The most common sequence variation in the human genome is the stable substitution of a single base, the single-nucleotide polymorphism (SNP). SNPs arise because of point mutations that are selectively maintained in populations. Most SNPs are 'silent' and do not alter the function or expression of a gene. The total number of SNPs in the human genome is estimated to be more than 10 million (3). Genomic instability has been characterized in many human cancers and its signature is the pattern of sequence deletions or rearrangements, frequently resulting in allelic imbalance. Until recently, efforts to capture global patterns of genomic imbalance have employed microsatellites, but the utility of dense SNP markers has been demonstrated in proof-of-principle studies. Global patterns of genomic imbalance can be detected by allelotyping of cancers, and point to regions where allelic imbalance could contribute to cancer. Since loss of heterozygosity (LOH) within one or more chromosomal region is a common form of allelic imbalance, sites of LOH can be investigated for the presence of tumor-suppressor genes. Studies in bladder, lung and prostate cancers have discovered previously unknown allelic imbalances in multiple sites using SNPs for LOH analysis (4,5 ). It is likely that patterns of LOH, through SNP analysis, could have diagnostic and prognostic implications. Specific LOH pattern could be correlated with expression array profiles to identify causal variants. Biomarkers. As the age of genomics proceeds forward in search of genetic variants (i.e. SNPs) that influence disease susceptibility and outcome, a great effort has been directed at picking Biomarker genes as markers for cancer progression and as diagnostic tools. The candidate gene approach examines SNPs, chosen from genes that 'make sense' or Biomarkers for a disease. In other words, they fit a plausible understanding of the biology. SNPs can also be chosen from a region previously identified by linkage study or gene expression analysis. Intense effort has focused on Biomarkers that alter protein function or gene expression. It has been estimated that there are perhaps 50,000-250,000 SNPs which confer a biological effect, most of which are distributed in and around the 30,000 genes (6,7,8). Pharmacogenomics. The accumulation of new information on various Biomarkers has propelled the field of Pharmacogenomics, which will bring about changes in the process of Drug Development. Genomics information will direct more personalized treatment regimens by identifying patients with genetic biomarkers who will be most likely to respond to a treatment and those who will respond adversely. Similarly, high-throughput genomic technologies will be increasingly used to identify Toxicology Biomarkers in Drug Development. Toxicology biomarkers will be crucial in identifying short-term and long-term genetic effects of drug-exposure. Currently, the use of Toxicology biomarkers is limited, but will play an important role in future clinical trials. The FDA is now encouraging Pharmaceutical industry to employ pharmacogenomics data in drug development to get a better understanding and reap the benefits of genomic analysis. Real-time quantitative RT-PCR as a high-throughput tool for Biomarkers and Pharmacogenomics studies. qRT-PCR provides a powerful technique for examining alterations in gene expression from virtually any type of biological sample. The assay comes with many advantages (high sensitivity, reproducibility, no post-PCR steps required and capability of high throughput) which makes it an attractive tool for biotechnological research in molecular diagnostics, gene function and pharmacogenomics. Research and molecular diagnostics laboratories have been implementing qRT-PCR over several years and the technique is becoming increasingly popular. The assay can employ different real time chemistries suitable for a particular study and budgets. Fluorescent dyes represent an economical approach for gene expression analysis. This approach can easily accommodate high-throughput gene expression analysis. Different types of hybridization probe chemistries are more expensive than fluorescent dyes due to manufacturing costs. Similar to fluorescent dyes, the hybridization probes can accommodate high-through put analysis. In addition, this approach also allows for the option of multiplexing. Using adequate instrumentation and correctly designed assays, up to four genes can be multiplexed, which further increases the throughput. Further, multiplexing allows for substantial sample savings which is beneficial when sample material is scarce. While the throughput for qRT-PCR is less than that of microarray based technologies, qRT-PCR offers currently unparalleled sensitivity in gene expression analysis, and this to a price affordable to most research facilities. Learn more at our Workshop on December 11th, 2004 in San Francisco. REFERENCES: Lander, E. S., Linton, L. M., Birren, B., et al. (2001) Initial sequencing and analysis of the human genome Nature 409, 860-921. Venter, J. C., Adams, M. D., Myers, E. W., et al. (2001) The sequence of the human genome Science 291, 1304-51. Botstein, D. & Risch, N. (2003) Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease Nat Genet 33 Suppl, 228-37. Dumur, C. I., Dechsukhum, C., Ware, J. L., et al. (2003) Genome-wide detection of LOH in prostate cancer using human SNP microarray technology Genomics 81, 260-9. Lindblad-Toh, K., Tanenbaum, D. M., Daly, M. J., et al. (2000) Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays Nat Biotechnol 18, 1001-5. Risch, N. (2001) Implications of multilocus inheritance for gene-disease association studies Theor Popul Biol 60, 215-20. Risch, N. & Merikangas, K. (1996) The future of genetic studies of complex human diseases Science 273, 1516-7. Risch, N. J. (2000) Searching for genetic determinants in the new millennium Nature 405, 847-56. *Please reference or credit any material, article or figure cited from http://www.medicineandbiotech.com as: Copyright 2004. MedicineandBiotech.com, http://www.medicineandbiotech.com/ Disclaimer: Please re-distribute MedicineandBiotech.com e-magazine. MedicineandBiotech.com does not assume, and hereby disclaim, any liability for any loss or damage caused by errors or omissions in any material published at the web-site http://www.medicineandbiotech.com, whether such errors or omissions resulted from negligence, misstatements or other oversights.

Integrative Genomics

By Dr. Neerja Sethi, Ph.D., Managing Editor, Email: editor@medicineandbiotech.com Volume 6. February 2005. In the post-genomic era, "Integrative Genomics" has become a buzz-word. Integrative Genomics has different definitions for different people. The healthcare and life-sciences industries prefer to call it the critical step towards "personalized medicine" –where genomics is integrated into the whole process of drug discovery and clinical research. The concept of personalized medicine aims at tailor-made therapeutics that match an individual’s genetic makeup. However, its important to understand that it may never reach the extent of "one individual-one target drug". Integrative Genomics represents integration of different technology platforms, including genomics, proteomics, high-throughput cell biology and Bio-IT leading to biological and clinical research data-integration. Integrative genomics offers the prospect of understanding the pathology of a disease at an individual’s genetic level and hence, allowing for target identification. Integrative Genomics will enable better design of clinical trials and its potential and benefits are gaining support from the Food and Drug Administration (FDA). Drugs are tested during clinical trials in a sub-population that is perceived to be the representative target population. In reality, there is a vast genetic diversity in sub-populations, much more than previously anticipated. Genomics or Pharmacogenomics will enable identifying an appropriate clinical trial population, where a drug delivers optimum results. Currently a number of clinical trials are ongoing in which a specific gene targeted by the drug is known and characterized. However, the clinical trials design does not take it into account finding a specific population which has the right target allele for the drug. It is possible that patients with certain other genetic factors might react unfavorably to the drug. In the next five years, hopefully, such genomic parameters will be taken into consideration for the development of safe and effective drugs. The concept of using an individual’s genetic makeup as a factor in deciding therapeutic treatment is referred to as pharmacogenomics. Pharmacogenomics allows identification of genetic variances in patients causing either adverse or favorable reaction towards certain compounds. These genetic markers or biomarkers are commonly found as small changes in DNA sequences in different individuals and are called single nucleotide polymorphisms (SNPs). In pursuit of personalized medicine, a study has been launched to characterize the genetic makeup of Asian populations by a collaborative effort of Asian scientists. The Pacific Pan-Asian SNP Initiative will study genetic variances of various Asian groups to identify why some clusters respond unfavorably to a drug or why some are more susceptible to certain diseases. This Project is conducted by the Human Genome Organization (HUGO). The countries participating in this project are China, India, Indonesia, Japan, Singapore and South Korea, with about 3000 participants who will provide blood samples for this study. The study will start in mid-2005 and may take two years to complete. Affymetrix, based in Santa Clara, California, will co-sponsor the study by providing a new microarray technology that will enable 50,000 SNPs analysis in each person. Results from this study will be available in public databases for various studies for a wide group of researchers. As a step towards personalized medicine, in November 2004, BiDil, a heart-failure drug developed by NitroMed (Lexington, MA), was shown to reduce death rates from heart diseases specifically in African-Americans. BiDil did not work effectively in the Caucasian populations. Approval of BiDil may be the first of its kind where a drug will be marketed for the use a specific race based on genetic factors responding to a particular drug. We have to keep in mind that besides genetic factors, other factors like environmental differences, habits, access to medical care, etc. also play an important role in a treatment outcome. Nonetheless, detecting individual genetic differences has a great potential value in detecting and treating disease. Towards this goal, Integrative Genomics will improve the process of drug discovery and development leading to effective treatment outcomes.