8 News 11(3–4) July 2001

Comparative Genomics

Model Organism Sequence and Function Studies Flourish odel organism genomes sequenced in the Human Genome Project (HGP) have helped researchers iden- Mtify many functionally important human DNA regions, including , and further studies will help elucidate fundamental biological processes common to all species. These organisms include the mouse, fruit fly, yeast, the bacterium Escherichia coli, and the roundworm. Outside the HGP, vast amounts of genomic data are being generated for a variety of microbial, animal, and plant systems. In this section are articles on the flowering plant Arabidopsis thaliana and the pufferfish Fugu rubripes, followed by those on the labora- tory mouse and an algorithm for comparisons of model organisms.à

New Genome Project Tackles Sushi Delicacy

cientists searching human genome comprises only about 400 million Sdata for genes and the DNA bases as compared with the 3.2 billion sequences that control their activity bases that make up human DNA. soon will have a valuable new resource, With far less noncoding (sometimes courtesy of the Japanese delicacy known as “junk”) DNA to sort known as Fugu (Fugu rubripes) or through, identifying biologically pufferfish. An international consortium, important regions in the Fugu led by researchers at the DOE Joint genome should be a much easier task. Genome Institute (JGI), has announced Comparing such DNA sequences from Black-Spotted Pufferfish. Photo by a collaborative agreement to sequence different species is an effective method Jeff Jeffords, http://divegallery.com the Fugu genome (www.jgi.doe.gov/ because evolution tends to conserve programs/fugu.htm). these regions. Although the Fugu genome contains JGI is generating draft sequences for Jazz, a new sequence assembler writ- essentially the same genes and regu- the Fugu genome project and applying ten at JGI. latory sequences as the human, it Sequence finishing and computa- tional annotation are being done with In the News other consortium members: U.K. Human Genome Mapping Project Role of Key Breast Cancer Identified (www.hgmp.mrc.ac.uk); Institute of esearchers Genevieve Nonet, Martha Stampfer, and Paul Yaswen at Molecular and Cell Biology, Singapore RLawrence Berkeley National Laboratory and Joe Gray, Koei Chin, and (www.imcb.nus.edu.sg); Molecular Colin Collins at the University of California, San Francisco, published an Sciences Institute, Berkeley article focusing on the functional characterization of the gene ZNF217 in (www.molsci.org/welcome.shtml); and the February 15th issue of Cancer Research 61. The gene is located in a Institute for Systems Biology, Seattle region of 20 found to have an increased copy number in many (www.systemsbiology.org). tumors, including 40% of breast cancer cell lines. Reintroduction of the ZNF217 gene into normal human breast cells in culture enables the cells to Pufferfish are raised in bulk on farms grow past the point at which they would normally stop. In addition to in Japan, where the taste is consid- becoming immortal, the epithelial cells containing ZNF217 gain several ered addictive. If prepared improp- other features characteristic of tumor cells, such as the ability to express erly, however, the flesh can be lethal telomerase. These results support the hypothesis that ZNF217 plays a role due to a highly potent neurotoxin in breast cancer by allowing the cells to continue growing and accumulat- present in Fugu ovaries, intestines, ing other changes necessary for malignant progression. à and livers. Eating pufferfish claims the lives of about 70 to 100 adventure- some (or unsuspecting) diners each Breast Cancer Researchers Use Gene Expressions year, most in rural areas and from sing gene-expression profiling, an international group of researchers led fish improperly cleaned at home. It is Uby Jeffrey Trent (NIH National Human Genome Research Institute) has the only food forbidden to be served made it possible to distinguish between hereditary and sporadic breast to Japan’s royal family. tumors for the first time. Simultaneous microarray assessments of some Fugu’s deadly effects have caught 6000 genes within breast cancer cells revealed clear and unique differences the imagination of many authors, in activity patterns, leading to a new test that shows exactly which genes including Ian Fleming. Near the end are active in a tumor cell. This capability may have important implications of From Russia with Love, the fic- for both diagnosis and treatment. The findings were published in the New tional James Bond is almost killed England Journal of Medicine 344(8), 539–48 (February 22, 2001). à by Fugu toxin.à July 2001 Human Genome News 11(3–4) 9

Comparative Genomics Plant Genome Significant to Agriculture, Energy, Human Health

or the first time, scientists have The complete sequence of Arabidopsis Fsequenced the complete genetic is directly relevant to human biologi- material of a plant, that of the mus- cal functions as well, because many tard weed Arabidopsis thaliana. The fundamental life processes at the international Arabidopsis Genome Ini- molecular and cellular levels are com- tiative (AGI) consortium published mon to all higher organisms. Some of the results and early analyses in the those processes are easier to study in December 14, 2000, issue of Nature, Arabidopsis than in human or animal Arabidopsis thaliana Source: National Science Foundation and articles are freely available on the models. Arabidopsis contains numer- Web through Nature’s Genome Gate- ous genes similar to those that prompt way (www.nature.com/genomics/ human diseases ranging from cancer with known functions. Strategies will papers/a_thaliana.html). and premature aging to ailments involve inactivating or over expressing such as Wilson’s disease, in which the each gene, one at a time, and observing Scientists expect that systematic stud- human body’s inability to excrete cop- the consequences. The NSF 2010 Proj- ies will illuminate numerous features per can be fatal. ect is part of a worldwide Arabidopsis of plant biology, including those of sig- functional genomics effort that will be nificant value to agriculture, energy, Gene Function Project coordinated in a manner similar to the environment, and human health. To help researchers capitalize on the Arabidopsis genome sequencing project. AGI, a collaboration of research groups genome sequence, NSF has begun the in the United States, Europe, and “2010 Project” to study the function of Data Japan, is funded by government agen- 26,000 Arabidopsis genes over the next For news, data, an interactive cies on three continents. U.S. research decade. Thus far, scientists have MapViewer, analysis tools, laboratory was supported in large part by DOE’s determined experimentally the roles protocols, and useful links, see The Office of Basic Energy Sciences, the of only about 1000, with another Arabidopsis Information Resource U.S. Department of Agriculture, and 14,000 estimated using computational (TAIR, www.arabidopsis.org). [Denise the National Science Foundation (NSF). methods to identify similarities of genes Casey, HGMIS]à Related to broccoli and cauliflower, Arabidopsis has emerged as a power- Drosophila Researchers Win Prize ful tool in plant molecular biology because of its rapid life cycle, small t its annual meeting in San Francisco on February 17, the American Asso- physical size, and relatively small Aciation for the Advancement of Science presented the prestigious Newcomb genome (125 Mb). The genome is orga- Cleveland Prize to five researchers representing the teams that completed the nized into 5 containing sequence of the fruit fly. Gerald Rubin and Susan Celniker accepted the prize on some 26,000 genes. Genes are compact behalf of the Berkeley Drosophila Genome Project (BDGP), and J. Craig Venter, and closely spaced (about 4.6 kb apart), Gene Myers, and Mark Adams represented Celera Genomics. BDGP is a suggesting short regulatory regions partnership among Lawrence Berkeley National Laboratory; the University compared with animal genomes. of California, Berkeley; and Baylor College of Medicine. Potential Applications The 2000 prize, which recognized an outstanding paper published in Science between June 1, 1991, and May 31, 2000, was awarded for “The Genome Having the entire genome will help Sequence of Drosophila melanogaster.” The paper is a series of articles jointly researchers identify plant-specific authored by hundreds of scientists, technicians, and students from 20 public and gene functions and develop rapid, sys- private institutions in 5 countries. It appeared in the March 24, 2000, special tematic ways to locate genes impor- issue (www.sciencemag.org/content/vol287/issue5461). tant for growing larger crops that are Celera and BDGP began a collaboration in 1998 to determine whether the more resistant to disease and weather whole-genome shotgun-sequencing method pioneered by Venter could be used on and produce useful chemicals more organisms having many thousands of genes encoded in millions of DNA base efficiently. Plants also hold great pairs. The technique, previously tested successfully in much smaller bacterial potential as sources of renewable genomes, proved in the larger fruit fly genome to be faster and more efficient à energy, although they currently repre- than traditional methods. sent just 3% of U.S. energy resources. Completion of the Arabidopsis genome Microbial Conference Set for Tennessee sequence is revealing new information on how photosynthesis converts solar he Ninth International Conference on Microbial Genomes will be held Octo- energy and carbon dioxide into biomass, Tber 28–November 1 in Gatlinburg, Tennessee (www.esd.ornl.gov/microbial_ helping scientists develop better genomes). Hosted by Jizhong Zhou and Oak Ridge National Laboratory, the plants for fuel and chemical uses. meeting will focus on DNA sequence, sequence comparison analysis, and recent advances in functional genomics. [Contact: Web site, [email protected], or [email protected]] à 10 Human Genome News 11(3–4) July 2001

Comparative Genomics ORNL Mouse Program Provides Powerful Tools for Studying Human Genes Connecting Sequence and Function equencing genomes was the easy Human Disease Models Spart. Some major challenges facing Two allelic mutations were recently the new era of post-sequencing biology discovered that serve as models for include finding all genes and deducing human acute and chronic tyrosinemia their functions, elucidating the con- (Aponte et al., Proc. Nat. Acad. Sci. nections between mutations and dis- USA 98, 641–45, 2001). The group Dabney Johnson and friend. ease, and untangling the complex also has identified a significant candi- Source: ORNL networks of interactions controlling all date gene for an obesity-associated these processes in living systems. quantitative trait locus that may have by N-ethyl-N-nitrosourea and Model organisms such as the mouse, an imprinted or maternal-effect com- cryopreserving both tissues and whose genes and DNA regulatory ponent (Dhar et al., Physiol. Genomics gametes. DNA or RNA from these regions are remarkably similar to 4, 93–100, 2000). mice can be used to screen for point those of humans, provide powerful mutations in any gene. The muta- tools for illuminating our own genetic MGG is evaluating specific candidate tions are identified by high-through- material. genes for induced mutations leading put heteroduplex analysis followed to (1) abnormal hematopoiesis (pro- by DNA sequencing of PCR products Researchers in the Mouse Genetics duction of red blood cells), iron trans- from this large bank. Stocks of mice and Genomics (MGG) section at Oak port, and skeletal development; (2) carrying the specific gene mutation Ridge National Laboratory (ORNL) abnormal brain function, resulting in can be reconstituted from the frozen are using mouse genetics and muta- epilepsy; (3) defective kidney function, gametes. An allelic series of mouse genesis strategies to annotate biologi- resulting in juvenile death; (4) mutations for any preselected gene cally important features of the DNA perinatal death, possibly due to skull then can be used to test specific sequence and to provide functional or brain abnormalities; (5) early hypotheses about the structure- information for parts of the genome embryonic death due to a failure of function relationships of the gene that are expressed or that regulate yolk-sac hematopoiesis; (6) defective product in the context of a specific gene expression (http://bio.lsd.ornl.gov/ skin function, leading to alopecia and genetic network or environmental mgd). A complementary effort exploits increased risk of skin cancer; and (7) response. Initial targets for this type genome data for a better understanding modification of the agouti signaling of analysis will include DNA-repair of normal and abnormal biological proc- pathway involved in pigmentation, and other types of radiation- and esses defined by genetic and phenotypic obesity, diabetes, and cancer. stress-response genes; intracellular- analyses of mouse mutations. Screening Libraries transport genes; regulatory regions of selected genes, including imprinted Mouse Mutations High-throughput mutation scanning MGG is screening about 10% of the ones; signaling molecules; and cancer- is central to these gene-discovery susceptibility genes. mouse genome for chemically induced efforts, so MGG is producing a large recessive mutations affecting a wide bank of 3000 to 5000 inbred User Facility variety of physiological, neurological, C57BL/6JRn mice. They will carry The Mouse Genetics Research Facility behavioral, morphological, develop- point mutations induced in their sires is a DOE Biological and Environmen- mental, reproductive, cancer, aging, tal Research User Facility, offering and other genetic phenotypes (http:// expertise in mouse genetics and muta- bio.lsd.ornl.gov/mgd/mutagenesis/ MicroCAT Scanner Used for Screening genesis, molecular biology, and func- mutagenesis.htmlx). This activity tional genomics. Mutant mouse stocks, expands on previous studies that iden- A high-resolution X-ray–computed mutagenesis and phenotyping proto- tified over 50 mutations associated tomography (CT) system developed at cols, and genomic expression and with visible or lethal phenotypes in 1% ORNL by Mike Paulus and Shaun phenotype data are available to the of this genome. The group is integrating Gleason provides researchers with a high-throughput method of internally functional genomics and wider bio- microarray and proteomics technologies logical research communities through into these and other mutagenesis screening mice for defects and dam- age resulting from mutations. The database, cryopreservation, and crosses for a molecular-based set of MicroCAT scanner, which generates mouse-distribution efforts at ORNL. assays to complement whole-organism 3-D images in 7 to 20 minutes, elimi- The Mutant Mouse Database pro- phenotypic screening. Point-mutation nates the need to sacrifice and dissect vides searchable, one-stop shopping maps describing single-base changes the mice. This allows researchers to for new and archived mutant-mouse of the target mutagenized regions are monitor ongoing changes in animals, thereby facilitating studies on disease stocks created over the program’s being merged with DNA sequence 50-year existence. [Dabney Johnson, maps to correlate mutant phenotypes progression, consequences of aging, and responses to therapies. ORNL, [email protected], with specific genes. http://bio.lsd.ornl.gov/mgd] à July 2001 Human Genome News 11(3–4) 11

Comparative Genomics Consortium Achieves Draft Mouse Sequence

n May the international Mouse 85% to 90% of gene sequences are directly into the genomes of mouse ISequencing Consortium (MSC) similar in mouse and human, with embryos. Many will develop into mice announced the completion of a draft similarities ranging from 60% to 90%. that show symptoms similar to those map (3× coverage) representing at of affected humans, thus facilitating In addition to highlighting gene least 95% of the mouse DNA sequence. studies and the development of new sequences, mouse-human DNA compar- MSC plans to use longer DNA therapies. isons will help identify other regions stretches of known map position and responsible for turning gene expres- The new mouse data already have assemble the sequence fragments into sion on and off. Genome comparisons been used to locate the mouse equiva- a finished, highly accurate form. The also will provide insights into the evo- lent of a human gene that may be mouse is an invaluable resource for lutionary mechanisms underlying related to schizophrenia. The discov- interpreting human genome data and overall gene organization. ery may help researchers develop a finding human genes and other func- mouse model to study further the tionally important DNA regions con- Like all mammals, humans and mice gene’s association with this devastat- served by evolution. share the same physiological systems ing mental disorder. à and develop many of the same dis- “The success of MSC and other public- eases. Because of its private research consortia no doubt will small size, high fer- lead to future cooperative efforts to tility rate, and ease solve big problems quickly, especially * NCBI Mouse Resources of manipulation, the when the resulting data belong in the Raw MSC data are freely available in the National public domain,” said Arthur Holden, offers great promise Center for Biotechnology Information Trace Archive cochairman of MSC. Comprising three (www.ncbi.nlm.nih.gov/Traces/trace.cgi) and in the in the study of the private companies and six NIH insti- Ensembl Trace Server (http://trace.ensembl.org). The genetic bases of dis- tutes, MSC was formed in October 2000. private company Celera Genomics also has generated ease susceptibility, a draft mouse genome sequence, which is accessible At 3 billion bases, the mouse genome development, and by subscription (www.celera.com). is comparable in size to that of humans. progress. Biotechno- The NCBI Mouse Genome Resources page (www.ncbi. Even more important, almost every logical methods now nlm.nih.gov/genome/guide/M_musculus.html) includes human gene appears to have a coun- allow DNA sequences the Graphical Mouse Genome Map Viewer for search- terpart in the mouse; among 4000 containing gene ing data by map position, gene symbol, gene name, or genes studied, fewer than 10 are pres- mutations associated marker name; Human-Mouse Homology Map; and ent in only one of the two species. with human diseases special BLAST form to facilitate searches of finished Researchers expect to find that about to be introduced mouse genome sequence.

Human-Mouse Comparisons Identify Candidate Sequences

A more detailed version of this article 19 (HSA19) nearly a year ago. Since human) and nonconserved features appeared in Science on July 6. then a DOE Joint Genome Institute distributed across the chromosome. (JGI) team headed by Lisa Stubbs at Comparison of related mouse and ess than 5% of the 3.2 billion bases LLNL has focused on functionally anno- HSA19 DNA identified more than in the human genome sequence is tating this chromosome, beginning with L 12,000 conserved sequence elements, thought to be occupied by genes, regu- an effort to identify and delineate all including candidate undiscovered latory elements controlling gene functional components of resident human exons (-coding gene expression, and other DNA regions genes. that serve important known biological fragments) as well as whole novel genes functions. One of the most efficient Spanning some 65 to 70 million bases and an estimated 4000 candidate reg- ways to identify these rare sequence and containing an estimated 1100 ulatory DNA sequences. Analyses features is to compare human DNA genes, HSA19 is one of the smallest, showed that highly conserved versions sequence with that of a related but yet most gene-dense, of the 24 human of virtually all single-copy human divergent species such as the mouse. chromosomes. To provide a tool for genes are found in mouse DNA and The power of the mouse model in functional annotation and evolutionary that mouse and human genes are studying human disease and in dissect- studies, the JGI-LLNL group isolated organized in very similar ways. and sequenced sets of overlapping ing gene function adds an important However, Stubbs and her team also BAC clones spanning mouse DNA dimension to such comparisons. noted striking species-specific differ- sequences related to HSA19. The draft ences in the content and functional A clone-based physical map assembled sequence’s high quality and solid capacity of certain types of genes, by scientists at Lawrence Livermore anchorage between human sequence including those encoding zinc-finger National Laboratory (LLNL) provided and related mouse clones enabled an transcription factors, olfactory the framework for completing the unusually comprehensive view of the draft sequence of human chromosome conserved (common to both mouse and (see Comparisons, p. 12) 12 Human Genome News 11(3–4) July 2001

Comparative Genomics

Comparisons (from p. 11) VISTA Software Widens Comparative View ith the increasing availability of cVISTA (complementary VISTA) is receptors, pheromone receptors, Whuman and mouse genomic used to look at differences between cytochrome P450, serine proteases, and sequence, a challenge confronting biol- such recently evolved species as mice many other types of . These ogists is how to convert these large and rats or humans and chimpan- types of genes, which often are found amounts of data into useful biology. One zees. rVISTA (regulatory VISTA) organized into tandem clusters of 5 to of the more powerful algorithms for iden- combines a search of the transcrip- more than 60, are present in different tifying functional regions in genomic tion-factor binding-sites database numbers and types in mouse and DNA, including both genes and sur- with comparative sequence analysis, human DNA. This reflects the very rounding regulatory elements, involves thus greatly reducing the number of active duplication, divergence, and comparative sequence analysis. predicted binding sites and suggest- either functional or total loss of genes ing plausible hypotheses for further since separation of rodent and primate Confronted by a scarcity of tools for such studies, investigators led by Inna biological studies. Used extensively lineages. Stubbs and her colleagues esti- in LBNL’s Genome Sciences Depart- mate that these changes have given rise Dubchak and Edward Rubin in the Genome Sciences Department at Law- ment, VISTA also has become the to at least 100 actively expressed genes main comparative sequence analysis that are unique to either humans or rence Berkeley National Laboratory (LBNL) have developed a suite of soft- tool of several large sequencing mice. These lineage-specific genes are centers. likely to have significant impacts on ware tools called VISTA (VISualization biology, defining at least some of the Tools for Alignment). Incorporating a Individuals can use VISTA by anony- major physiological, morphological, and novel global-alignment procedure and mously sending sequence data to the behavioral differences between rodents components for visualization and anal- Web site (www-gsd.lbl.gov/vista) or and primate species. ysis, VISTA enables large-scale com- requesting a stand-alone computer parisons between DNA sequences of program (free for academic institu- HSA19 is related to mouse DNA found two or more species. Its visual output tions; modest licensing fee for private in 15 conserved segments from differ- is clean and simple, allowing for easy industry). More than 250 investiga- ent portions of mouse chromosomes 7, identification of conserved regions. Simi- tors have used VISTA online since it 8, 9, 10, and 17. Because both human larity scores are displayed for the entire became available in July 2000, and and mouse sequences were derived sequence, thus helping in identification close to 150 copies of the program from precisely mapped clones, the JGI of shorter conserved regions or regions have been distributed in academic team could identify the boundaries or with gaps. institutions of 20 countries. [Edward “breakpoints” of these 15 homology seg- Rubin, LBNL, [email protected]] à ments and examine the sequence con- Various modifications of VISTA deal tent and structure of the chromosome- with particular biological problems. rearrangement sites. Repeated sequences including clustered gene family mem- bers, LINE1, retrovirus sequences, and MGI Release 2.7 Enhances Allelle Detail Searching local duplications were found at all breakpoint sites. Results of this study ouse Genome Informatics (MGI) of a spontaneous or genetically indicate that, throughout evolution, Mprovides integrated access to data engineered allele; “Molecular “illegitimate” recombination (i.e., recom- on the genetics, genomics, and biology Information” reference describing of the laboratory mouse (www.informa- bination of related DNA sequences at or identifying the molecular tics.jax.org). Release 2.7 incorporates nature of the mutation responsi- nonhomologous chromosomal sites) the following enhancements to the ble for a given phenotypic allele; between gene families and other dupli- “Allelle Detail” page. cated sequences has driven evolution- and “Synonym References” con- New query field for “Promoter taining an allele synonym). ary changes in chromosome structure. Notes” can be used to search for “Gene Expression in This Mutant” The JGI team is now extending these when and where a transgene is expressed. includes the number of assays, studies to comparisons of related regions with a link to a display on the in a nonmammalian vertebrate species, “Molecular Information” (previously “GXD Expression Summary” page the chicken. Together with JGI’s emerg- “Molecular Description”) section of all expression data assayed in ing sequence of the pufferfish and other may include mutations, ES cell line mice carrying the allele. The vertebrate genomes being sequenced by and strain, promoter, notes (molecu- “Allele Detail” page no longer dis- public efforts worldwide, these studies lar), and reference (molecular). plays the mode of inheritance if it will provide the basis for deeper evolu- References associated with a is not applicable. tionary and functional studies of the esti- phenotypic allele used experimen- Allele Query Form: www.informa- mated 1200 HSA19 genes. The resulting tally or included as a major part of a tics.jax.org/searches/allele_form.shtml data and resources will be used to iden- review article are added. The page Help document on Using the Allele tify all HSA19 genes and their regulatory also displays three other kinds of Query Form: www.informatics.jax. elements and pave the way for studies of references (“Original Reference” org/userdocs/allele_help.shtml à biological function in model organisms. reporting the creation or discovery [Lisa Stubbs, DOE JGI and LLNL] à July 2001 Human Genome News 11(3–4) 13

In the News Converting Energy to Medical Progress Although typically focused on only one part of DOE’s Biological and Environ- Some Highlights of BER-Funded Research mental Research (BER), Human Genome News will now include material in Nuclear Medicine from the Medical Sciences Division Brookhaven National Laboratory, New York (MSD), which shares the same mission. One of the world’s leading laboratories for the design, synthesis, and applica- MSD’s nuclear imaging has all but elim- tion of radiopharmaceuticals for such priorities as substance abuse, aging and inated the need for exploratory surgeries. degenerative diseases, and the biology of tumors. Following is a summary of MSD’s new Lawrence Berkeley National Laboratory, California booklet, Converting Energy to Medical Specialized instrument development to improve detection of prostate, breast, Progress (April 2001). The booklet is and other cancers for such priorities as SPECT imaging for brain studies of available from HGMIS and can be mental illness. New radiotracers to study aging, heart disease, and cancer. downloaded from the Web Oak Ridge National Laboratory, Tennessee (www.doemedicalsciences.org). Genesis of BER when ORNL made available a vast selection of radionuclides for nuclear medicine research. Studies of new radiopharmaceuticals’ potential for uclear medicine is an exciting diagnostic and therapeutic applications in cancer and coronary artery disease. Nfield in healthcare that provides important information for diagnos- Memorial Sloan-Kettering Cancer Center, New York ing, evaluating, and managing dis- Pioneering work in the use of “monoclonal antibodies” to treat cancer. Novel ways to produce a variety of radionuclides to treat lymphoma, leukemia, and ease. Virtually all hospitals, as well prostate cancer. as many clinics and doctors’ offices, conduct nuclear medicine tests and University of California, Los Angeles scans. About 13 million (35,000 a New ways to image the biology and genetics of several diseases, including can- cer, diabetes, heart disease, Alzheimer’s disease, and Parkinson’s disease. Pio- day) such procedures are performed neers in PET and microPET, which allows scientists to watch cells at work in each year on patients in the United the living person or mouse. States (and many more in other Washington University, St. Louis, Missouri countries) in cardiology, oncology, Innovative use of radionuclides in medicine. Important contributions to PET. neurology, sports and internal medi- Development of new organic carrier molecules and a new class of PET radio- cine, thyroid disorders, surgery, gas- pharmaceuticals based on metal radionuclides and first hormone receptor agents. trointestinal ailments, pulmonary University of Michigan, Ann Arbor disorders, infection, and dementia. Research in the chemical design and synthesis of radiopharmaceuticals and Nearly every nuclear medicine scan or their implementation in PET and SPECT brain-chemistry studies. Development test used today was made possible by of computer science for nuclear medicine imaging systems. Insight into several research funded by BER and its pre- neurological disorders that affect movement, memory, aging, and dementia. decessor agencies on radiotracers, radiation-detection devices, gamma cameras, positron emission tomogra- abnormal biochemical (physiological) process of disease, and even the molec- phy (PET) and single-photon emission changes. With its unique ability to ular errors that cause disease. computed tomography (SPECT) scan- reveal biochemical processes, nuclear Radiotracers interact with such biological ners, and computer science. medicine provides crucial information processes as bone mineral turnover, about numerous diseases. Nuclear In managing DOE’s nuclear medicine potassium transport in heart muscle, or medicine procedures are different from research program, MSD pursues two glucose metabolism in various organs X rays, scans by computed tomography main areas of scientific investiga- or tumors. Highly sensitive scanners (called CT) and magnetic resonance tion—imaging systems and detect and process the energy signals, imaging (called MRI), and ultra- radiopharmaceuticals (radiotracers). after which computer programs recon- sound, all of which primarily visual- The aim is to develop beneficial appli- struct them into diagnostic images. ize structure and shape (anatomy). cations of nuclear technologies for PET and SPECT, for example, produce medical diagnosis and treatment of Nuclear medicine images are produced 3-D images that look like multiple slices many diseases. by low levels of energy emitted from through the body. medically useful radiotracers intro- Biological Imaging Imaging Gene Expression All human characteristics depend on a duced into a patient’s body. SPECT gives off gamma rays and PET emits BER scientists have successfully cre- galaxy of biochemical reactions that ated images of genetically altered organ occur many millions of times per min- positrons, another form of energy that converts to gamma rays. Radiotracers function in animals. Now, MSD has ini- ute within the cells and tissues of the tiated exploratory research to develop body. A deranged chemical process can are designed to provide insights about cause disease, resulting in other healthy, normal biology, the biological (see Imaging, p. 14) 14 Human Genome News 11(3–4) July 2001

In the News

Toxicogenomic strategies under National Center for Toxicogenomics development through NCT are based on microarrays containing he outpouring of human genome To develop the field of toxicogenomics thousands of messenger RNA Tdata and the development of and coordinate an international (mRNA) fragments, the intermedi- large-scale, rapid, efficient technolo- research effort, the NIH National ary products of active genes, to cre- gies to probe them have transformed Institute of Environmental Health ate “gene-expression profiles.” Using the field of toxicology and engendered Sciences (NIEHS) created the bioinformatics tools, researchers a new specialty—toxicogenomics. National Center for Toxicogenomics combine these data with those from Researchers in this new field study (NCT). NCT aims to promote protein-expression profiles to deter- gene response to environmental advances in toxicogenomics and mine how disease may be influenced stressors and toxicants and seek to catalyze their application to the pre- by environmental factors. NCT’s understand the role played in disease vention and amelioration of environ- goal is to combine these microarray- by gene-environment interactions. mentally related diseases (www.niehs. based strategies into a unified The use of DNA microarray and nih.gov/nct.org.htm). approach, together with the infor- proteomic techniques to assess The establishment of NCT was matics infrastructure necessary to changes in gene and protein expres- announced in December 2000 by understand it. sion is a rapidly growing research NIEHS Director Kenneth Olden and area that will have a large impact in Deputy Director Samuel Wilson. NCT many areas, including the environ- (see Toxicogenomics, p. 15) Director is Raymond Tennant, NIEHS. mental health sciences.

Imaging (from p. 13) new radiotracers based on messenger can identify new molecular targets for Future Impacts RNA for dynamic imaging of gene imaging the biological activity of dis- The nuclear medicine of tomorrow expression in animals in real time. ease. In time, drugs may be custom will depend on the discovery of BER researchers at Sloan-Kettering, made for individual patients based on radiopharmaceuticals that seek spe- for example, created iodine-124 FAIU, genetic “fingerprinting,” and nuclear cific molecular and genetic targets, a highly specific radiopharmaceutical medicine will play a crucial role in this the design of companion advanced that provides the first nuclear medi- pursuit. scanners for creating meaningful cine images showing the expression of PET imaging techniques developed at images, and the promise of new certain genes in tumors in a live Washington University, for example, radiopharmaceutical treatments for animal. à are helping to identify which patients cancers and genetic diseases. As scientists discover more informa- with breast cancer will respond to tion about the relationship between tamoxifen hormone therapy. Scien- genes and disease or behavior, they tists there also have developed fluo- rine-18 fluoroestradiol that targets estrogen receptors on breast tumors. The presence or absence of PET Developers Win abundant estrogen receptors in Kettering Prize breast cancer cells can help doctors select the most appropriate chemo- avid Kuhl (University of Michi- therapy for these patients. Dgan, Ann Arbor) and Michael Phelps (University of California, Since mice can be engineered biolog- Los Angeles, School of Medicine) ically to carry genes that produce are co-winners of the Charles F. disease, molecular probes such as Kettering Prize for their involvement microPET allow the imaging of dis- in the development of positron emis- ease initiation and progression in a Miniature PET sion tomography (PET). The living mouse. In concert with this scanner, the Kettering Prize, sponsored by the research, scientists are investigat- “microPET” for imaging mice, General Motors Cancer Research ing highly sophisticated drugs developed at Foundation, recognizes the most out- designed to correct the molecular the University standing recent contribution to the errors of disease. Combined with of California, diagnosis or treatment of cancer. the explosive growth of knowledge Los Angeles, Both researchers have long-standing from genome research, PET and with scan inset. BER research support involving PET microPET play a major role in the and its medical applications for diag- promising new era of molecular nosis and therapy.à diagnostics and therapeutics.