Corrections

MEDICAL SCIENCES. For the article ‘‘HLA-B*5801 allele as a BIOGRAPHY, . For the article ‘‘Biography of Cornelia genetic marker for severe cutaneous adverse reactions caused by I. Bargmann,’’ by Melissa Marino, which appeared in issue 9, allopurinol,’’ by Shuen-Iu Hung, Wen-Hung Chung, Lieh-Bang March 1, 2005, of Proc. Natl. Acad. Sci. USA (102, 3181–3183; Liou, Chen-Chung Chu, Marie Lin, Hsien-Ping Huang, Yen- first published February 22, 2005; 10.1073͞pnas.0500025102), Ling Lin, Joung-Liang Lan, Li-Cheng Yang, Hong-Shang Hong, due to an editorial office error, the term ‘‘roundworm’’ was Ming-Jing Chen, Ping-Chin Lai, Mai-Szu Wu, Chia-Yu Chu, incorrectly replaced with ‘‘flatworm’’ in the first sentence. The Kuo-Hsien Wang, Chien-Hsiun Chen, Cathy S. J. Fann, Jer- correct sentence should read as follows: ‘‘In the unhearing, Yuarn Wu, and Yuan-Tsong Chen, which appeared in issue 11, unseeing world of the roundworm , its March 15, 2005, of Proc. Natl. Acad. Sci. USA (102, 4134–4139; is its lifeline.’’ first published March 2, 2005; 10.1073͞pnas.0409500102), due to ͞ ͞ ͞ ͞ a printer’s error, the symbols in the affiliation line appeared www.pnas.org cgi doi 10.1073 pnas.0502717102 incorrectly. The corrected affiliation line appears below.

aInstitute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Departments of cDermatology, eRheumatology, Allergy, and Immunology, and hNephrology, Chang Gung Memorial Hospital, Taipei 10507, Taiwan; fDepartment of Medical Research, Mackay Memorial Hospital, Taipei 10449, Taiwan; gDepartment of Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung 40705, Taiwan; iDepartment of Dermatology, National Taiwan University Hospital, Taipei 10002, Taiwan; jDepartment of Dermatology, Taipei Medical University Hospital, Taipei 11031, Taiwan; kDepartment of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan; lDepartment of Pediatrics, Duke University Medical Center, Durham, NC 27710; and dMolecular Medicine Program, Taiwan International Graduate Program, Academia Sinica and the School of Life Sciences, National Yang Ming University, Taipei 11529, Taiwan

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0502360102 CORRECTIONS

www.pnas.org PNAS ͉ April 26, 2005 ͉ vol. 102 ͉ no. 17 ͉ 6237–6238 Downloaded by guest on September 25, 2021 MICROBIOLOGY. For the article ‘‘Symmetrical base preferences surrounding HIV-1 and avian sarcoma͞leukosis virus but not murine leukemia virus integration sites,’’ by Alexander G. Holman and John M. Coffin, which appeared in issue 17, April 26, 2005, of Proc. Natl. Acad. Sci. USA (102, 6103–6107; first published March 31, 2005; 10.1073͞pnas.0501646102), the au- thors note the following: ‘‘After our report appeared in the PNAS Early Edition, we observed that the simultaneously published paper by Wu et al. (1) reported similar base prefer- ences for all integration sites; however, the placement of the integration site in the analysis of the murine leukemia virus (MLV) data set differed by one base. Further analysis revealed a small initial error that propagated through our analysis, ultimately leading us to misplace the location of the MLV integration site by one base. As a consequence, the MLV integration site preferences incorrectly appeared to be asym- metric. We now conclude that HIV-1, avian sarcoma͞leukosis virus (ASLV), and MLV all show symmetrical base preferences surrounding their integration sites. Accordingly, the title of the article should be corrected to read ‘Symmetrical base prefer- ences surrounding HIV-1, avian sarcoma͞leukosis virus, and murine leukemia virus integration sites,’ and it has been cor- rected in the online version. Fig. 2 and Figs. 11 and 12, which are published as supporting information on the PNAS web site, can be corrected by placing the integration site between offset 0 and 1 instead of Ϫ1 and 0. A corrected version of Fig. 4 and its legend appear below. The remainder of the analysis was unaffected by this error, and with the described correction, we remain confi- dent in our overall conclusions.’’

1. Wu, X., Li, Y., Crise, B., Burgess, S. M. & Munroe, D. J. (2005) J. Virol. 79, 5211–5214.

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0502810102

Fig. 4. Comparison of the observed integration preferences to the inferred preferences for the opposite LTR. (A) Schematic of the topology of HIV-1 integration. HIV-1 integration complexes join the viral LTRs to opposite strands of the DNA separated by five bases. MLV joins with an offset of four bases, whereas ASLV uses a six-base offset (not pictured). (B) Symmetry observed in HIV-1 with five-base offset. Black lettering represents the base preference seen from the top LTR (Fig. 1).The integration site is indicated by the black dashed vertical line in the graph and the black arrow in the numbering schematic. The vertical arrow indicates the expected axis of sym- metry based on the characteristic five-base spacing between the sites of HIV-1 DNA integration. The red lettering represents the same base preferences; however, they are reversed and shifted five bases to represent the preferences as observed from the bottom LTR. The inferred integration site is indicated by the red vertical line in the graph and the red arrow in the numbering schematic. (C) Symmetry observed in MLV with four-base offset. (D) Symmetry observed in ALV with six-base offset.

6238 ͉ www.pnas.org Downloaded by guest on September 25, 2021 Biography of Cornelia I. Bargmann BIOGRAPHY

n the unhearing, unseeing world man tumors?’ everyone would have said of the flatworm Caenorhabditis me. Including me!’’ admits Bargmann. elegans, its sense of smell is its In the years that followed, other re- I lifeline. Cornelia Bargmann’s searchers found that neu gene was am- work has revealed many of the genetic plified in aggressive breast tumors. The and molecular underpinnings of receptor, also called HER2 or erbB2, is C. elegans olfaction and has furthered now the target for the Herceptin (trastu- the understanding of its influence on zumab) antibody, which is used to treat complex behaviors. Additionally, Barg- metastatic breast . Although mann has uncovered key signaling path- Bargmann was not involved in develop- ways that direct the proper wiring of the ing trastuzumab, she states, ‘‘It’s gratify- nematode’s 302 . ing to have been involved in a discovery Previously at the University of that, within your lifetime, results in a California, San Francisco (UCSF), Barg- patient therapy.’’ mann recently moved to The Rock- efeller University (New York), where Sniffing Out Olfaction she is a Howard Hughes Medical Insti- After receiving her Ph.D. from the De- tute investigator, Torsten N. Wiesel Pro- partment of in 1987, Bargmann fessor, and head of the Laboratory of remained at MIT for postdoctoral re- Neural Circuits and Behavior. Barg- search in the laboratory of H. Robert mann’s research has been recognized Horvitz. She began to pursue a long- through numerous awards, including the standing interest in the nervous system Lucille P. Markey Award (1990–1995) and behavior. Although she felt intimi- and the Searle Scholar Award (1992– dated by the complexity of the nervous 1995). She was elected to the American system, an exchange with David Balti- Academy of Arts and Sciences in 2002 Cornelia I. Bargmann. Photograph courtesy of more, an MIT faculty member and No- and the National Academy of Sciences Carly Calhoun. bel laureate, jolted her into action. in 2003. When Baltimore asked about her re- In her Inaugural Article in this issue discipline that would provide the foun- search interests, Bargmann replied that of PNAS (1), Bargmann maps out the dation for her later research career. she was interested in the molecular biol- neural circuit underlying navigation in In 1981, Bargmann graduated from ogy of the nervous system but did not C. elegans—from the neurons involved the with a degree know how to approach it. ‘‘He said, in the initial detection of food odors in and headed north to ‘Well, you’re not very brave, are you?’’’ to the motor neurons that control the attend graduate school at the Massachu- worm’s movement. This article presents setts Institute of Technology (MIT, one of only a few behaviors that have Cambridge, MA). ‘‘My first job in a been mapped in such a detailed way. Surprising Success science lab was the Academic Destiny NEUROSCIENCE As a graduate student, Bargmann stud- Growing up in Athens, GA, in a family ied the molecular mechanisms of onco- world’s most menial she describes as ‘‘frighteningly well edu- genesis in the laboratory of Robert summer job— cated,’’ Bargmann took an early liking Weinberg, who focused on Ras genes to her science classes in junior high and and their role in human tumors. Barg- making fly food.’’ high school. ‘‘I always loved science mann became involved in these proj- more than anything else because of the ects and helped identify the mutation ‘blue collar’ aspect of it—the fact that that activated Ras in human bladder she recalls laughingly. ‘‘That is not you actually do it,’’ she says. Bargmann’s cancer (2). something a 20-year-old needs to hear first major foray into scientific research Bargmann’s own thesis research on a from a Nobel laureate.’’ was during her undergraduate years at non-Ras , called neu, turned Emboldened by Baltimore’s provoca- the University of Georgia (Athens, GA), out to have surprising clinical relevance. tive comment, Bargmann told Horvitz where her father was a professor of After cloning the neu oncogene from a that she wanted to study chemosensory Computer Science and Statistics. At 17, rodent neuroblastoma and determining behavior in C. elegans, the model system ‘‘my first job in a science lab was the that it was an epidermal growth factor used by Horvitz’s laboratory. Horvitz’s world’s most menial summer job— receptor (EGFR)-related protein (3), policy with his postdoctoral fellows was making fly food for a population biology Bargmann then described the mutations such that ‘‘we could work on anything lab,’’ Bargmann recalls. The laboratory that activated neu (4). Although the ro- that we wanted to, any biological prob- head, Wyatt Anderson, took an interest dent neuroblastoma model was consid- in Bargmann, introducing her to Sidney ered an interesting experimental model lem, as long as we could address it in Kushner in the Genetics Department. system, no human correlate was known,

During her junior and senior years, she making its relevance to human cancer This is a Biography of a recently elected member of the worked in Kushner’s laboratory, study- dubious. ‘‘If you had asked anyone in National Academy of Sciences to accompany the member’s ing bacterial genetics and RNA metabo- the Weinberg lab, ‘Whose project is Inaugural Article on page 3184. lism and learning , a least likely to result in a therapy for hu- © 2005 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0500025102 PNAS ͉ March 1, 2005 ͉ vol. 102 ͉ no. 9 ͉ 3181–3183 C. elegans,’’ says Bargmann. In her read- sory could express at least four born from stimulating the appropriate ings of nematode biology, Bargmann different receptor genes, which could ex- neuron. found that, in the 1970s, researchers had plain the worm’s diverse sense of smell As Bargmann continued to probe shown that the worms could respond to (8). Because C. elegans has only 14 types C. elegans’ olfactory system, her work chemical stimuli and undergo chemo- of chemosensory neurons but can respond began uncovering the mechanisms of taxis. However, little was known about to dozens of different chemicals, each more complex behaviors. Because each the genetics of these behaviors, and neuronal type was believed to detect mul- chemosensory neuron could detect a Bargmann thus saw an opportunity to tiple stimuli. Bargmann helped confirm number of different odorants, she be- pursue her interests. this by describing over 40 divergent lieved that C. elegans could discrimi- In her first study in Horvitz’s labora- GPCRs, in gene clusters of two to nine nate between those compounds. Using tory, Bargmann used laser ablation to members, that could contribute to such a forward genetic screen, Bargmann’s show that certain sets of chemosensory functional diversity. laboratory identified a mutant able to neurons in C. elegans were important for In genetic screens of olfactory recog- detect and respond to different odor- responding to various chemicals (5). She nition and signal transduction, Barg- ants but lacking the ability to discrimi- also identified sets of chemosensory mann identified odr-10, which proved to nate between them (12). Studies of the neurons that controlled whether the be a bona fide receptor for a single mutant phenotype showed that the worm entered into and exited from an odorant, diacetyl (9). Mutants of odr-10 worm could discriminate odorants by alternative stage, called a dauer larva, could not detect diacetyl, which is pro- segregating the detection of different that does not eat or reproduce and is duced by lactobacilli (a food source of odors into two distinct but similar ol- highly resistant to stress (6). C. elegans) and is normally attractive to factory neurons. The gene responsible Bargmann achieved another research the worm. Upon cloning the odr-10 for this mutant phenotype, nsy-1, was breakthrough by elucidating the depth gene, Bargmann found that it encoded a later found to regulate neuronal asym- and breadth of the nematode’s olfactory novel GPCR. This study was hailed as metry and diversity. sense. She showed that C. elegans could Although Bargmann and her group detect and respond to a number of vola- generally studied laboratory-induced tile chemicals, which acted as either at- mutations, they also wanted to increase tractants or repellents. Through laser One gene that their understanding of the natural ge- ablation, Bargmann found that chemo- varies among normal netic variation in complex behaviors, taxis to volatile compounds required such as why different populations of different sensory neurons compared individuals accounted C. elegans in the wild exhibit either soli- with chemotaxis to water-soluble attract- tary or social feeding behavior. Barg- ants, providing some of the first evi- for a major behavioral mann showed that such differences in dence that C. elegans had a sense of feeding behavior were due to different smell. In addition, she identified muta- difference. isoforms of the npr-1 gene, which en- tions in the odr genes that disrupted codes a homolog of the neuropeptide Y chemotaxis to some chemicals (7). At receptor (13). The social feeding strain C. elegans the time, was known to re- providing the first direct biological dem- carried one isoform, NPR-1 215F, spond to a few amino acids and salts, whereas the solitary feeders possessed onstration that a specific GPCR recog- but Bargmann began to realize that the isoform NPR-1 215V. When NPR-1 nized a specific odorant. nematodes ‘‘had a sense of smell that 215V was expressed in the social feeding The defining factor in whether an odor- detected hundreds, maybe thousands, of strain, the worms’ behavior changed to ant was attractive or repellent did not lie different odors.’’ that of solitary diners. This result in the receptor itself, but in the sensory showed that one gene that varies among A Brainy Environment neuron in which it was located. Bargmann normal individuals accounted for a ma- In search of a faculty position, Barg- and colleagues demonstrated this in a jor behavioral difference. mann found that UCSF offered abun- 1997 paper in which they expressed the Bargmann later discovered that envi- dant expertise in the field she loved but ODR-10 receptor in neurons that nor- ronmental factors also govern social lacked formal training in—neuroscience. mally detect repellant compounds (10). feeding in C. elegans. ‘‘We’ve known Impressed with UCSF’s rich neuro- This misplaced receptor caused the ani- that all animals can aggregate under science environment and the general mal to avoid diacetyl, a previously pre- certain conditions, but we didn’t know enthusiasm for science of the faculty, ferred odorant. This result suggested that what was acting as a sensory trigger for Bargmann accepted an assistant profes- specific behavioral responses are wired to aggregation,’’ she says. ‘‘We’ve found sor position in the Department of Anat- individual olfactory neurons. ‘‘It’s not that recently that one of those signals is oxy- omy in 1991. Over the next 13 years, there isn’t learning or experience in be- gen.’’ With colleague Michael Marletta Bargmann was promoted through the haviors,’’ says Bargmann, ‘‘but there is a of the University of California, Berke- ranks to full professor (1998) and served pre-patterning of appropriate behaviors.’’ ley, Bargmann identified a guanylate as vice chair of the department (1999– In 2002, Bargmann and colleagues illus- cyclase homolog as the molecule respon- 2004). trated this prewired behavior by introduc- sible for sensing oxygen and generating At UCSF, Bargmann continued to ing a foreign receptor, the mammalian the behavioral response to undesirable study how olfaction works at the molecu- receptor for capsaicin, into C. elegans neu- oxygen levels (14). They demonstrated lar level. Taking advantage of newly avail- rons (11). Because C. elegans does not that social feeding requires the activity able information about the C. elegans naturally have any ion channels that react of this molecule, and such feeding oc- genome, Bargmann identified large fami- with capsaicin, they normally have no curs only when oxygen exceeds the nem- lies of G protein-coupled receptors reaction when exposed to it. However, atode’s preferred level. (GPCRs) that appeared to be chemosen- placing the mammalian receptor into the sory receptors for water-soluble attract- nematode’s repellant-detecting neurons Back to Basics ants, repellants, and pheromones. She caused the worm to avoid capsaicin. In addition to elucidating the molecu- showed that a single type of chemosen- Therefore, a new artificial behavior was lar mechanisms underlying C. elegans

3182 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0500025102 Marino nervous system function, Bargmann is Bargmann acknowledges the impor- the worm’s sinuous navigational path to also investigating the genesis of the tance of collaborators such as Tessier- find food. ‘‘I’ve been trying to do this ex- BIOGRAPHY brain. ‘‘We wanted to have a deep un- Lavigne in her research career. ‘‘At least periment since I was a postdoc,’’ she says. derstanding of the system we worked half my papers have been published to- Jesse Gray, a graduate student of Barg- in,’’ she says. ‘‘That requires under- gether with at least one other group,’’ mann’s and the lead author of the article, standing the development of these she says. ‘‘It’s great because it allows me ‘‘was able to figure it out by conceptualiz- neural circuits.’’ In 1998, Bargmann’s to engage my dilettantish interest in ing the problem in the right way....Ifeel laboratory identified and cloned the many things without having to sacrifice that he’s been able to talk to the neurons gene sax-3 (Robo), which functions as high standards.’’ in their own language.’’ a receptor in axon guidance (15). Even with such a seemingly simple In the laboratory next door, Marc Connecting the Dots system, C. elegans’ sense of smell con- Tessier-Lavigne, currently senior vice From genetics to behavior, Bargmann tributes to a vast diversity of behaviors. president of Research Drug Discovery has identified key pieces of the puzzle of Understanding this system may con- at Genentech (South San Francisco, olfactory function in C. elegans.Inher tribute to understanding more complex CA), was also studying axon guidance, Inaugural Article (1), Bargmann pre- mammalian systems and will surely as well as the molecules that guide ver- sents an entire neural circuit for C. el- keep Bargmann occupied for many tebral axonal growth. Bargmann and egans navigation, which has been done years. ‘‘When you work on C. elegans, Tessier-Lavigne began a long-term col- only a few times for simple withdrawal people are always asking you if you’re laboration, which continues to produce and escape behaviors. ever going to work on vertebrates,’’ she insight into the molecules that match In this PNAS study, Bargmann took says. ‘‘But I actually think this is a axons with their appropriate targets advantage of having ‘‘a wiring diagram for great system for studying behavior.’’ (16–18). Bargmann recently demon- the worm brain’’ and used that schematic, Studying behavior in a vertebrate strated that neurons establish their con- with laser ablation, ‘‘to trace a path from model such as the mouse is ‘‘just too nections with the help of other cells and a sensory input all the way to the differ- complicated—they’re too smart, they’ve molecules that act as guideposts, such as ent motor outputs that generate behav- got too much on their minds,’’ says the synaptic guidepost protein SYG-2 iors.’’ By ablating different sets of neurons Bargmann. ‘‘A worm, maybe I can and its receptor SYG-1 (19, 20). SYG-1 one at a time, then removing the nema- figure out.’’ acts as a matchmaker by allowing the todes from their food source, Bargmann correct connections to form between and colleagues were able to determine Melissa Marino, neurons. which neurons governed each aspect of Freelance Science Writer

1. Gray, J. M., Hill, J. J. & Bargmann, C. I. (2005) 8. Troemel, E. R., Chou, J. H., Dwyer, N. D., Colber, 15. Zallen, J. A., Yi, B. A. & Bargmann, C. I. (1998) Proc. Natl. Acad. Sci. USA 102, 3184–3191. H. A. & Bargmann, C. I. (1995) Cell 83, 207–218. Cell 92, 217–227. 2. Tabin, C. J., Bradley, S. M., Bargmann, C. I., 9. Sengupta, P., Chou, J. H. & Bargmann, C. I. 16. Hao, J. C., Yu, T. W., Fujisawa, K., Cullotti, J. G., Weinberg, R. A., Papageorge, A. G., Scolnick, (1996) Cell 84, 899–909. Geneyo-Ando, K., Mitani, S., Moulder, G., E. M., Dhar, R., Lowy, D. R. & Chang, E. H. 10. Troemel, E. R., Kimmel, B. E. & Bargmann, C. I. Barstead, R., Tessier-Lavigne, M. & Bargmann, (1982) Nature 300, 143–149. (1997) Cell 91, 161–169. C. I. (2001) Neuron 32, 25–38. 3. Bargmann, C. I., Hung, M.-C. & Weinberg, R. A. 11. Tobin, D. M., Madsen, D. M., Kahn-Kirby, A., 17. Yu, T. W., Hao, J. C., Lim, W., Tessier-Lavigne, (1986) Nature 319, 226–230. Peckol, E. L., Moulder, G., Barstead, R., Maricq, M. & Bargmann, C. I. (2002) Nat. Neurosci. 11, 4. Bargmann, C. I., Hung, M.-C. & Weinberg, R. A. A. V. & Bargmann, C. I. (2002) Neuron 35, 307–318. 1147–1154. (1986) Cell 45, 649–657. 12. Wes, P. D. & Bargmann, C. I. (2001) Nature 410, 18. Gitai, Z., Yu, T. W., Lundquist, E. A., Tessier- 5. Bargmann, C. I. & Horvitz, H. R. (1991) Neuron 698–701. Lavigne, M. & Bargmann, C. I. (2003) Neuron 37, 7, 729–742. 13. de Bono, M. & Bargmann, C. I. (1998) Cell 94, 53–65. 6. Bargmann, C. I. & Horvitz, H. R. (1991) Science 679–689. 19. Shen, K. & Bargmann, C. I. (2003) Cell 112,

251, 1243–1246. 14. Gray, J. M., Karow, D. S., Lu, H., Chang, A. J., 619–630. NEUROSCIENCE 7. Bargmann, C. I., Hartweig, E. & Horvitz, H. R. Chang, J. S., Ellis, R. E., Marletta, M. A. & 20. Shen, K., Fetter R. D. & Bargmann, C. I. (2004) (1993) Cell 74, 515–527. Bargmann, C. I. (2004) Nature 430, 317–320. Cell 116, 869–881.

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