Fostering Communication and Collaboration
The nihCatalyst A Publication for NIH Intramural Scientists
National Institutes of Health Office of the Director b Volume 15, Issue 4 July-August 2007
Bethesda Makes Another Name for Itself The New Kid in Town CC, NIAID Researchers Uncover New Disease-Causing Bacterium
- A buffered-cbarcoal yeast-extract (BCYE) plate showing the very first isolate o/Granulibacter bethesdensis -
Ernie Branson
Lab Sleuths: (left to right, back row) Patrick Murray, Adrian Zelazny, David E. Greenberg, and Steven Holland; (front row) Li Ding, Frida Stock, and Alexandra Wong
staining reveals a Gram gram- by Christopher Wanjek acid-producing bacteria never before negative coccobacillus, but standard associated with human disease. The microbiology laboratory procedures ethesda, the healing bath bacterium’s close are cannot identify the bacterium famed cousins used com- of ancient Jerusalem and present- mercially in the production of vinegar. B day home in Maryland to a cer- The discovery also highlights the tain collection of health institutes, has unique combination of talent and re- acquired one more historic attribute: sources at NIH, in particular the close
There’s now a bacterium named after it. relationship among the CC’s microbiolo- The newly identified bacterium is A pair of the newly discovered continued on page 6 bacterium up close called Granulibacter bethesdensis, a trib- to the neighborhood where dis- ute the CONTENTS covery was made. 1 8-12 After a three-year investigation, re- CC-NIAID Team Interest Group searchers at NIAID and the CC deter- Uncovers New Directory mined that this bacterium was the cause Pathogen 13 of lymphadenitis in a patient with the Here’s Looking At Events rare genetic immune disorder known as The New Kid in Town chronic granulomatous disease (CGD). 14 15 2 AOS Viewpoint: The finding underscores bacteria-dis- Gene sequencing and biochemical Guest Editorial— Beware Erosion ease connections that still await discov- OITE Director: Of Freedom of inquiry profile reveal bacterium family, and ery. On Attracting further biochemical tests show the The Best Postdocs 15 19 It took some sleuthing. G. bethes- bacterium can grow on methanol Recently Tenured (right), a clue to its natural environ- densis is difficult to culture and is not 4-5 ment only a new species but constitutes a Exhibit: 20 The Art of Science/ Kids’ Catalyst: images courtesy of Adrian Zelazny whole new genus in a family of acetic- On Track All That Fizz The NIH Catalyst
Guest Editorial: From the Director, OITE
Postdocs: The Bread and Butter of NIH Research
’e all know what a great postdoc can do in the intramural research program, and heard for a lab. Postdocs can bring new per- from current postdocs, members of FELCOM, and Wspective and energy to our research pro- recent alumni about professional and career de- grams; they can lead the charge in developing velopment opportunities at NIH. They left not new technologies and establishing new collabo- only with a positive impression of NIH in gen- rations; they can help maintain a positive lab en- eral but also with a better appreciation of the
vironment and provide outstanding mentoring importance of NIH intramural research. It is for summer students, postbacs, and grad students. hoped that the attendees will share their positive Strong postdocs also can be critical scientific impressions with their colleagues at their home colleagues who help us maintain our focus and institutions, generating even more highly quali- strengthen our research programs. As the CC's fied postdoctoal applicants for NIH openings. Sharon Miigram Patrick Murray describes in the first-page story The event was highly successful from both
in this edition of The NIH Catalyst, the NIH is sides; many Pis were excited about the quality "blessed with bright fellows" who indeed enable of the students they had met, and some of the many of the discoveries here. participants are now on campus working as The OITE works in collaboration with NIH ICs postdocs. Ninety-seven percent of festival attend- to oversee the recruitment and training of more ees who responded to a survey at the end of the than 3,800 postdocs, along with hundreds of event said that they would recommend the festi- graduate students, medical students, clinical fel- val to a friend, and 71 percent said they were lows, postbacs, and summer interns. These young likely or very likely to accept a postdoctoral po-
scientists often advance to be leaders in their sition at NIH if one were offered.
chosen fields. Among NIH training alumni are All participating NIH Pis agreed that this is a several Nobel Prize winners and dozens of mem- cost- and effort-effective way to recruit and in- bers of the National Academy of Sciences. terview potential postdoctoral fellows. That said, identifying postdoc candidates and Plans are well underway for our second NGSRF,
recruiting the very best of them to our labs is not which will take place October 11 and 12. More always easy. Many new Ph.D. graduates have than 600 applications were received, and we ex- multiple offers and many outstanding opportu- pect to invite up to 250 students to attend the nities, making postdoc recruitment a frustrating festival. Applicants come from nearly 200 research and time-consuming task. institutions across the country and express inter-
I hope to share with you an NIH-wide plan to ests ranging from nanotechnology to global public
improve this system, which is off to a good start, health, from tracking proteins to mapping the and call upon you to keep the momentum go- brain, and from molecular biology to behavioral ing. In summer 2005, a committee of IC training studies. directors and representatives of the OITE devel- You can help make the coming festival even oped a plan to address the challenge of recruit- more successful than last year's. Perhaps some ing top postdocs. The committee proposed a two- attendee—or attendees, for that matter—would
day festival to the scientific directors that would be a great fit with your lab? I encourage you to bring 250 outstanding advanced graduate students find out by participating in the festival. Go to the to NIH. OITE website In October of 2006, that plan was implemented
2 — July — August 2007
‘O Pioneers!’: A Day to Celebrate the Visions of Pioneer Awardees AND ANNOUNCE THE NEWEST RECIPIENTS
ne researcher is using methods vative, and potentially Mil DIRK' TOR'S whose cutting-edge re- O rooted in physics and engineering transformative, re- search represents an to understand the emergence of autoim- search. important element of mune diseases. Another is crafting new The goal is to iden- the NIH portfolio.” ways of observing protein folding in- tify scientists whose The symposium will side living cells. And a third aims to ideas could have espe- begin at 8:15 a.m. with build a catalog of the microbial organ- cially significant impact opening remarks by isms inhabiting the human body to help but whose research Zerhouni and Jeremy explain the roles of these communities proposals may be too Berg, NIGMS director, in health and disease. novel or untested to who oversees the Pio- These scientists are among the 13 re- fare well in the tradi- neer Award program. cipients of the 2006 NIH Director’s Pio- tional peer-review pro- The symposium will neer Award who will report on their cess. conclude with a poster research progress at the third annual Researchers at all ca- session and concurrent Pioneer Award Symposium on Wednes- reer levels and working reception from 3:30 to day, September 19. in a broad range of dis- 5:30 p.m. The posters During the event in the Natcher Con- ciplines—from engi- will showcase the work ference Center (Building 45), NIH Di- neering and mathemat- of the 2004, 2005, and rector Elias Zerhouni will also announce ics to the behavioral 2006 Pioneer Award re- the newest group of awardees. The sym- and social sciences cipients and members posium agenda is at are encouraged to ap- A-W-A-R-D of their labs.
Attendance is free and registration is not “The Pioneer Award supports particu-
Upcoming Talks by Last Year’s Awardees
he talks by last year’s year’s awardees at the third annual NIH Director’s Pioneer Award Symposium, Sep- Ttember 19 at Natcher Conference Center, will begin at 8:50 a.m. and end at 3:30 p.m. (with breaks and lunch interspersed). The speakers and the titles of their talks are: Karla Kirkegaard, Stanford University School of Medicine, Stanford, Calif.: “Dominant Drug Targets in RNA Viruses” Evgeny Nudler, New York University School of Medicine, New York: “New Approaches to Fight Bacterial Infections” David Reiman, Stanford University: “It’s a Jungle in There: Explorations of the Human Microbiome” Kwabena Boahen, Stanford University: “Neurogrid: Emulating a Million Neurons in the Cortex” Younan Xia, University of Washington, Seattle: “Putting Nanostructures to Work for Biomedical Research" Aaip Chakraborty, Massachusetts Institute of Technology, Cambridge, Mass.: “Understanding Adaptive Immu- nity and Its Aberrant Regulation: A Crossroad of the Physical, Life, and Engineering Sciences” Lila Gierasch, University of Massachusetts, Amherst: “Moving the Protein Folding Problem from the Test Tube to the Cell” Gary Pielak, University of North Carolina at Chapel Hill: “Protein Biophysics Linder Physiological Conditions” Thomas Kodadek, University of Texas Southwestern Medical Center at Dallas: “Monitoring the Immune System with Synthetic Molecule Microarrays: A New Route to Biomarker Discovery” Rosalind Segal, Dana-Farber Cancer Institute, Boston: “Proteoglycan Interactions with Sonic Hedgehog Are Selectively Required for Mitogenic Responses” James Sherley, Massachusetts Institute of Technology: “Making Human Adult Stem Cell Expansion Routine” Rebecca Heald, University of California, Berkeley: “Elucidating Mechanisms of Intracellular Scaling” Cheng Chi Lee, University of Texas Health Science Center at Houston: “Suspended Animation of Non-hiber- nating Mammals”
3 The NIH Catalyst
A Different Kind Of Peer Review
Photos and text by Christopher Wanjek
isit the Clinical Center this summer, and you’ll find that NIMH is working on ducks; NIDCR Vhas reached a breakthrough on water lilies; and NIAID is perfecting quilts. These institutes haven’t changed research priori- ties. Rather, their researchers, exercising the other side of their brain, have created paintings, photographs, stained glass, and even origami for a new juried art Scientists (and others) appreciate the art of 30 of their colleagues at the exhibit called “Art Loves Science,” on display in the opening reception June 14 of the Art Loves Science exhibition , which runs Clinical Center until August 15. through August 15 at Gallery 3, first floor of the CC Medicine and the arts have long intermingled. Paint- ings have graced the cover of JAMA since 1964 to emphasize the humanities in medicine. Many doctors, if not patrons of
NHLBI’s Deanne Alpert, the impetus behind the show, Viruses dance on quilts NIAID’s Meggan Czapiga transforms a tape dispenser into a work of art for
the arts, are active participants, as exemplified by the NIH Philharmonia and the NIH Community Orchestra.
So it is perhaps not so strange that some NIH researchers have set aside their Matrigel medium for the more fanciful media of gouache and canvas.
The Clinical Center is well known for its contemporary art, an eclectic mix of media comprising about 3,000 original pieces mostly from local artists, displayed in eight galleries and along the building’s vast network of corridors. The CC has its own art director, Crystal Parmele, who oversees procurement. Cu- rator Lillian Fitzgerald designs and installs the exhibits and handles art sales. This latest exhibit, however, is the first to feature the art of NIH researchers exclusively. Deanne Alpert, a postbac in NHLBI interested in painting and drawing, came up with the idea for an all-scientist ex- hibit upon realizing there were many musical programs at the NIH featuring local talent but nothing for the visual arts. She ultimately identified 30 other artists at the NIH interested in participating in a juried art show. Many of the artists, like Alpert, draw inspiration from their scientific work. Alpert said that studying stained subcellular objects under the microscope has revealed striking shapes, NHGRI’s Tyron Spady and his portrait of canine behavior patterns, and color combinations that she never would have
4 July — August 2007
On Tenure Track
Ivan Ovcharenko is devising zebrafish embryos. Encouragingly, computational methods to cut many of the predicted elements were through the so-called junk DNA in found to be driving gene expression the human genome to find gene- in the heart region of developing regulatory elements concealed mice and fish. within. Ovcharenko uses gene-expression He joined the NCBI’s Computa- profiling, transcription factor bind- tional Biology Branch this year af- ing-site analysis, and comparisons ter working as a scientist at the among vertebrate genomes to deci- Lawrence Livermore National Labo- pher sequence signatures for tissue- ratory in Livermore, Calif., for four specific enhancers and repressors in years. With only about two percent the human genome. A major moti- of the three-billion-letter human vation for coming to the NIH was genetic code known to correspond “the possibility to establish collabo- to proteins, his task of identifying rations with researchers doing mo- and characterizing elements that lecular biology and clinical studies,” regulate genes, hidden somewhere he said. in the remaining 98 percent of the He sees a direct link between un-
human genome, appears arduous. David Gilbert, DOE/Joint Genome Institute derstanding the genomic encryption But Ovcharenko has had some of gene regulators, often referred to Ivan Ovcharenko early success in applying evolution- as the second code of genomes, and ary comparisons and sequence pat- predict patterns in nature and then developing disease screening tech- tern analysis techniques to predict partnering with molecular biologists to niques and ultimately cures, pro- the location of gene regulators in test his theories. vided he gets together with the right so-called gene deserts—megabase- He and his colleagues from the Uni- bunch of researchers. long stretches of DNA completely versity of Chicago and the Lawrence Ber- Ovcharenko is now working with devoid of protein-coding genes. keley National Laboratory in Berkeley, researchers in NICHD, among other Ovcharenko, who holds a doctor- Calif., for example, have devised a com- ICs. An overview of his recent work
ate in physics and mathematics, con- putational strategy to identify regulatory is captured in a cover article from ducts his research much like a theo- elements governing heart development February 2007 in Genome Research retical astrophysicist, using keen in- during embryogenesis and to test them entitled “Predicting tissue-specific sight and computational muscle to in vivo in transgenic mouse and enhancers in the human genome.” — Christopher Wanjek
visualized otherwise. (Her piece in the show, a painting called “Tape Dispenser,” admittedly didn’t reflect this influence, but may have very well been inspired by the office supply shortage a few months ago.) Tyrone Spady, a postdoc in NHGRL has a photograph of his dog on display, called “Nya.” His canine photographs were fea- tured on several news media websites, such as ScienceNow and NPR, supporting the discovery by Elaine Ostrander’s NHGRI lab of genes related to dog size and the muscle development of whippet race dogs. Spady studies canine behavior and is inspired by photographing the emotional complexity of dogs. None of the pieces on display have overt scientific themes, aside from a quilt made by Meggan Czapiga, a staff scientist in the NIAID Biological Imaging Facility. Czapiga said she Finds beauty in the color and shapes of viruses. Her quilt incorporates images taken straight off the confocal microscope of respiratory syncytial virus, the most common cause of bronchiolitis and pneu- monia among infants. A few of the researchers participating in the exhibit have ex- tensive art training. Larry Bauer, a nurse consultant with the CC Patient Recruitment and Public Liaison Office, has a bachelor’s degree in Fine arts. His piece, called “Succulent #1,” is a large, computer-enhanced photograph of a desert succulent. His use of saturated color produces a fantastical, dreamlike effect that makes the flower simultaneously familiar, even edible, yet all the while Photo-enhanced enchanting desert generated by the otherworldly. flower, CC’s Larry Bauer The “Art Loves Science” exhibit is on the first floor of the Clini- cal Center in Gallery 3 near the lobby for PET and nuclear medi- Ed. Note: Exhibit art appears in color in the online Catalyst. cine. H
5 2 1 1 3 The NIH Catalyst
New Disease-Causing Bacterium
continued, from page 1
gists and clinical investigators, who typi- cally visit the microbiology lab every T • Acetobacter aceti NCIMB 862 (X74066) day to discuss their patient’s infections. 58 “People are finding new bacteria all — Gluconobacter oxydans NCIMB 901 T (X73820) the time,” said David Greenberg, an as- 62 sociate clinical investigator in the NIAID T Saccharibacter floricola DSM 1 5669 (AB1 10421) Laboratory of Clinical Infectious Dis- 51 eases (LCID) and lead author on two — Asaia bogorensis NRIC 031 T (AB02S928) 86 papers describing the new bacterium. 1, - Swaminathania salitolerans PA51 T (AF459454) A Rare Find 66 T “But to find an organism that actu- Kozakia baliensis NRIC 0488 (AB056321) ally causes human disease, albeit in an T - Neoasaia chiangmaiensis AC28 (AB208549) immunocompromised population, is rare. That’s what makes this very excit- 61 - Acidomonas methanolica JCM 6891 T (D30770) ing.”
Greenberg and his colleagues, led by T • Gluconacetobacter liquefaciens NBRC 12388 (X75617) Steve Holland, LCID chief, are now try- ing to understand what makes this bac- Granulibacter bethesdensis CGDNIH1 1 (AY788950) terium virulent to CGD patients and whether it is implicated in other, more Acidiphilium cryptum ATCC 33463 T (D30773) 83 common diseases. 66 T They also hope to determine what Acidocella facilis ATCC 35904 (D30774) the immunodominant antigens are in 7 order to develop a screening test. Such -Acidisphaera rubrifaciens JCM 10600 (D86512) CGD research has provided insights into T the nature of inflammation and immu- Rhodopila globiformis DSM 1 61 (D86513) nology. Craurococcus roseus JCM 9933 T (D85828) People with CGD are susceptible to 53 serious infections of the lungs, lymph Paracraurococcus ruber NS89 T (D85827) nodes, skin, and bone from seemingly unrelated bacteria and fungi. The CC is 51 T - Roseomonas gilardii ATCC 49956 (AY1 50045) the leading research facility studying
CGD, which affects about one in T — Roseococcus thiosulfatophilus DSM 851 1 (X72908) 250,000 people worldwide.
The CGD patient, who has since Stella humosa DSM 5900 T (AJ53S710) largely recovered but continues to be 0.01 monitored, was first referred to the CC in 2003 after his doctors in his home- From D.E. Greenberg, et al., November 2006 (see footnote 2) town could not determine the cause of Sequencing of the 16s rRNA gene revealed that Granulibacter bethesdensis his swollen lymph nodes. constituted its own branch
Step 1: Culturing Traditional laboratory staining dem- Adrian Zelazny, then a Fogarty fellow Biopsies of the patient’s lymph nodes onstrated this was a gram-negative bac- in the microbiology lab, to pursue other were sent to to the microbiology lab, terium, but standard biochemical tests techniques lor identifying the bacte- where Alexandra Wong, a medical tech- couldn’t pinpoint its identity. rium. nologist in the CC’s Department of For many labs, had they even been Laboratory Medicine, first discovered able to culture this bacterium, this point Step 2: Sequencing the bacterium growing in cultures of would have been the end of the road. Zelazny’s first approach was to se- the biopsies. The CC-NIAID team, however, was quence the bacterium’s 16S ribosomal Because many patients who come to confident that it was dealing with some- gene, now a well-established test in the the CC are immunocompromised and thing unique and not simply a lab con- microbiology lab. These results were susceptible to a wide variety of infec- taminant. The same bacterium was iso- the first clue of the organism’s unique- tions, culture conditions are optimized lated from multiple biopsies, and gram- ness. Upon sequencing, the team found for detection of bacteria that grow negative bacteria are not common lab that the closest match was the slowly or are fastidious. This was for- contaminants. Acetobacteraceae family, bacteria tunate because this bacterium took five So after consulting with Holland and known to convert alcohol into vinegar.
days to grow, about twice as long as Greenberg, Patrick Murray, chief of “It still wasn’t a very good match, so most bacteria. clinical microbiology at the CC, asked early on we had a sense we were deal-
6 — July-August 2007
I
ing with something gen, and how do you new,” Greenberg said. prove that?”
“The question is, how Murray attributed it to do you figure out if being “blessed with you’re dealing with a bright fellows” and brand new species—or “given the resources to genus, for that matter?” pursue interesting re- Zelazny, today a staff search.” scientist in Holland’s “There are a tremen- lab, subjected the mys- dous amount of dis- tery bacterium to more eases in the world for biochemical tests and which there is no compared the results to known etiology,” those from tests on the Greenberg said. “And Acetobacteraceae fam- people have been sus- ily. picious that there may The team found that be an infectious con- the bacterium ex- nection. ... At the end pressed unique biologi- of the day there are dis- cal signatures. He then ease-causing organisms performed a polyphasic that remain to be dis- taxonomic study, which covered. People should Dave Dorward, Rocky Mountain Labs, NIAID looks at the sequence of be on the lookout for many genes, not just Scanning electron micrograph of a neutrophil about to engulf a them.” 16S. The final tests in- Granulibacter bethesdensis cluster cluded DNA-DNA hy- What’s in a Name? bridization, a technique to measure the Further proof came after the team The naming of the new organism genetic distance between the new bac- placed the sequence information into carried out by Greenberg, Zelazny, Hol- terium and members of the GenBank and word spread about the land, and Murray—was nearly as tricky Acetobacteraceae family. bacterium. G. bethesdensis was isolated as its discovery. “The bacterium emerged as a distinct from two more CGD patients with lym- The four liked the way Granulobacter branch,” Zelazny said, and the combi- phadenitis at the CC and from a fourth bethesdensis rolled off the tongue, and, nation of sequencing and biochemical patient with lymphadenitis in Houston. indeed, in the first published paper, is-
1 tests “proved it was a new member in Working with Frida Stock, a research sued April 2006, they proposed this the Acetobacteraceae family.” assistant in the microbiology depart- name. But by the time the second pa- 2 The outstanding question that re- ment, the group has found that all the per was issued, in November that year, mained was whether G. bethesdensis organisms are genetically distinct. they had been informed that
was the culprit causing lymphadenitis. Greenberg is summarizing the four Granulibacter, with an z, is the proper Once again, the CC could accommo- case studies in a third paper. So far, G. word to accompany the Latin mascu- date. bethesdensis has not been isolated from line adjective bethesdensis—and the the environment, but similar organisms name was changed accordingly. Step 3: grow on sugar cane and tropical fruit, Fungi are even harder to name, Demonstrating Pathogenicity essentially high-sugar environments Murray joked. H Years ago, Holland’s lab had created where natural fermentation yields al- a mouse model for CGD, a well-stud- cohol for the bacteria to feed on. Three ied of the four patients are from sunny inherited disorder of phagocytic Footnotes cells caused by a defect in the phago- climes; one is from tropical Panama. 1. D.E. Greenberg, L. Ding, A.M. cyte NADPH oxidase, an enzyme re- The original patient is from the north Zelazny, F. Stock, A. Wong, V. Ander- sponsible for creating the reactive oxi- but developed his disease shortly after son, et al. “A novel bacterium associ- dant superoxide. a visit to the Bahamas. ated with lymphadenitis in a patient with Li Ding, a assistant in senior research chronic granulomatous disease,” PLoS Holland’s lab, exposed the enzyme-de- Many More Out There Pathogens 2, 28 April 14, 2006; online).
ficient mice to G. bethesdensis and, sure “Why was [G. bethesdensis] discov- 2. D.E. Greenberg, S.F. Porcella, F. enough, the mice developed a pathol- ered here?” Greenberg asked. “Probably Stock, A. Wong, P.S. Conville, PR. “ ogy similar to that of the original pa- because we have a spectacular micro- Murray, et al., Granulibacter bethes- densis gen. nov., sp. nov., a distinctive tient. More important, she could re-iso- biology lab. We have the means not pathogenic acetic acid bacterium in the late the bacterium and grow it again, only to identify things when they arise, family Acetobacteraceae." Int. ]. Syst. demonstrating how G. bethesdensis but to take it to the next level and start Evol. Microbiol. 56, 2609 (2006). multiplied in the mice. asking questions: Is this really a patho-
7 .
Annual Update Interinstitute Interest Group Directory
Web Access Structural Biology Interest Group Bioethics Interest Group Meeting time and place (2006-07): Usually Meeting time: 1st Monday (except 3rd Although not all the sites are up 3rd Thursday, 4:00 pm, Building 50, first Monday following holidays; usually does to date, nearly all the Interest floor conference room; notices by e-mail not meet during summer), 3:00 pm Groups have websites that can be and on the SBIG website Meeting place: Natcher, Room D, or
< : / / accessed through http Contact 1: Anna Panchenko Building 31, conference room; check www.nih.gov/sigs/ sigs.html>) Phone: 301-435-5891 yellow sheet or web«site E-mail:
8 July-August 2007
Chromatin and Chromosomes Interest Data Resources Sharing Interest Group Drug Discovery Interest Group Group Meeting time: 4th Wednesday, 3:00-4:30 pm Meeting time: Usually one Thursday a Meeting time: One Tuesday a month, 4:00 pm Meeting place: Rockledge 1 (6705 month, 3:00 pm Meeting place: Building 41, Conf. Room Rockledge Dr.), Room 5147 Meeting place: Building 37, 6th-floor Contact: David Clark Contact 1: J.P. Kim conference room (Rm. 6041) Phone: 301-496-6966 Phone: 301-435-0679 Contact: John N. Weinstein E-mail:
Contact 2: Marilyn Millet- E-mail :
Contact 1: Juan Lertora Meeting/Videoconference: Natcher, RoornJ; 6701 Democracy Blvd., Suite 710 Phone: 301-496-9425 GRC (Baltimore), Room 1E03; FCRDC, Contact: Alexis Bakos E-mail:
Contact 1: Daniela Verthelyi Meeting place: Porter Neuroscience E-mail:
Fluorescence Interest Group Head and Neck Cancer Interest Group Integrative Neural-Immune Interest i Hi Meeting time: Usually even Fridays, 4:00 Meeting time and place: To be announced Group ill a pm; see website; join to receive upcoming Contact 1: Wendy Weinberg Meeting time and place: To be announced H
Jli events e-mail Phone: 301-827-0709 Contact: Socorro Vigil-Scott 1
' Meeting place: Building 10, usually Room E-mail: < [email protected]> Phone: 301-496-9255 | Co 5N264 Contact 2: Carter Van Waes E-mail:
10 7 1 July-August 2007
Mass Spectrometry Interest Group Mood and Anxiety Disorders Phage-Tech Interest Group Meeting time: 1st & 3rd Thursday, 10:30 Interest Group Meeting time and place: Varies am (check website) Meeting time: Tuesday, noon, 12-18 times Contact Rotem Edgar Meeting place: Building 10, Room 7S235 a year Phone: 301-451-8820 Contact: Dawn Maynard Meeting place: Varies (once speakers are E-mail:
11 — The NIH Catalyst
Interinstitute Interest Group Directory
** Signal Transduction Interest Group ** Tobacco and Nicotine Research Women’s Health Special Interest Meeting time: Alternate Wednesdays, 5:00 pm Interest Group Group Meeting place: 5 Research Court, Conf. Room Meeting time: 4th Wednesday, every other Meeting time: One Friday every other
Contact 1: John Northup month, 2:00 pm (next meeting is July 27) month, September through June, 11:30 Phone: 301-496-9167 Meeting place: 6701 Rockledge Dr., Rooms am— 12:30 pm
E-mail:
Contact 2: John Kylan Lynch Phone: 301-402-7144 Phone: 301-451-7968 E-mail:
1 1 :00 am Contact 1: Alison McBride Contact 3: Warren Strober Meeting place: Building 35, Room BB1000 Phone: 301-496-1370 E-mail:
Contact: Bai Lu E-mail:
Phone: 301-435-2970 Contact 2: Carolyn Wilson Peter Basser is planning on starting an E-mail:
12 .
July — August 2007 a Celebrating Global Disease Control
September Gala: NIH Research Festival Celebrates Its 20th Anniversary
he 2007 NIH Research Festival, to be held September 25—28, 2007, on the T NIH Bethesda campus, also commemorates the 20th anniversary of this NIH Intramural Program showcase event. This year's organizing committee is co-chaired by Alan Koretsky, NINDS, and Dan Longo, NIA. The opening plenary session on Tuesday, September 25, at 9:30 a.m. in Masur Auditorium, features presentations on "Chromosomes in Modern Biol- Evan Galloway ogy and Medicine." Food for thought Other events during this four-day showcase of the NIH Intramural Program include cross-cutting symposia and poster sessions; the 2008 FARE awards ooks—especially when they’re free ceremony and reception; special exhibits on resources for intramural research; B and filled with vital health informa- the job fair for NIH postdoctoral, research, and clinical fellows; the festival tion— “can save lives,” Roger Glass, di- food and music fair; and the Technical Sales Association scientific equipment rector of the Fogarty International Cen- tent show. ter at NIH, told a gathering of interna- All NIH investigators and Bethesda FDA/CBER investigators are invited to tional scientists, economists, and health submit poster abstracts online through July 30. Posters in any area of research policy experts who came to NIH June conducted within the NIH Intramural Program will be considered for presenta- 1 1 to review the goals and accomplish- tion, but the organizing committee requests a limit of one poster submission ments of the Disease Control Priorities per first author. Applicants will be notified of acceptance by e-mail in mid- Project. August. The occasion was the one-year anni- For a preliminary schedule of events and online poster registration, go to the versary of the project’s influential pub- NIH Research Festival website at lication: Disease Control Priorities in De-
13 The NIH Catalyst
From the Assembly of Scientists: Viewpoint
Ed. note: The following commentary represents the views of the author and appears here under the auspices of the NIH Assembly of Scientists, which has been accorded a standing ViewPoint space in The NIH Catalyst. Individuals who wish to write a column should contact a member of the ViewPoint editorial board (Abner Notkins, Harvey Alter, Edward Korn, Alan Schechter, Joshua Zimmerberg).
Erosion of Freedom of Inquiry
’hat would tenured scientists get of intramural investigators These boards are made view as true freedom of in- generally are in the hands of up of extramural scientists Wquiry? a single individual— the sci- who, ironically, criticize in- The answer simply put: To wake up entific director—the pressure tramural scientists for not in the morning with a new idea for an to conform to the changing choosing “high-risk, high- experiment in one’s area of expertise thrust of an institute rather impact” projects, but pun- and to initiate that experiment the same than to pursue one’s own re- ish them when the projects day with available resources and with- search ideas can be great. The do not provide outstanding out having to seek administrative ap- lack of a readily available for- results. This, too, dimin- proval. mal appeal process for inves- ishes free choice.
In fact, it is this unencumbered free- tigators who feel that their As in all fields of en-
dom to explore ideas that has led so budgets are inadequate or deavor, science too has its many individuals into science as a ca- have been inappropriately re- trends and fads that gener- reer. The Intramural Research Program duced adds further pressure to conform, ate infusions of money from public and (IRP) at NIH for years has represented as does the lack of the option — avail- private funding agencies. The scientific the best of this tradition—and still does able to extramural scientists— to seek community rewards investigators in today. But this tradition is under con- funds from other public or private agen- these areas with invitations to present stant direct and indirect attack and re- cies. their work at meetings and publish their quires vigilant protection. Along the same line, candidates for papers in prestigious journals. Ironically, direct threats to freedom tenure-track positions know that to be Such actions can result in an exodus of inquiry sometimes come from the selected they must come up with projects from true independent investigator-ini- very source that deserves so much that will be viewed as relevant to the tiated research to trend-conformity. The credit for making American science the particular institute’s current direction. scientific journals also contribute to this envy of the world, the U.S. government. From the institute’s point of view this problem by favoring trendy papers, Unfortunately, political consider- certainly seems to make good sense, but even to the exclusion of solid and im-
ations at times inform funding deci- it may not take full advantage of the portant papers in other areas. sions, leaving scientists to choose to candidate’s scientific curiosity, creativity, Some scientists and administrators pursue either those well-funded re- and expertise—nor does it allow for truly have added further to the problem by search areas that are in current politi- free choice of projects. taking the position that tenure, promo- cal favor or some poorly funded line Similarly, “big science” projects are tion, and support require publication of research that they consider more revolutionizing biological research and in so-called high-impact journals (for achievement of specific Cell). promising. expediting the example, Science, Nature,
The IRP can create its own political goals, but at a price. Invariably, these It certainly is not the intention of the problems. In an effort to satisfy an projects limit freedom of inquiry for in- scientific community or the journals to institute’s often vocal extramural com- dividual members of the “big science” dampen creativity or freedom of in- munity and patient constituency, mis- research teams. quiry—and they almost certainly would sion-oriented and translational studies The threat to freedom of inquiry is not dispute this accusation — but the end frequently are favored over investiga- just politically and administratively based, result is subtle, and often not so subtle, tor-initiated basic and long-term re- but also can come from the scientific pressure on investigators to follow the search that doesn’t have an immediate community itself. The peer-review pro- trend. payoff. cess that has proved so important in Of factors that place restrictions on This emphasis pressures scientists evaluating the contributions of individual projects that an investigator might wish within an institute to conform to cur- scientists and in maintaining the high to pursue, one of the most distressing
rent priorities and can restrict curios- quality of science can sometimes be one is the increasing bureaucracy that has ity-driven freedom of inquiry. Seren- of the culprits. evolved in government and academia dipitous findings also may create a di- Study sections are reluctant to support in recent years. lemma: Instead of pursuing unexpected novel ideas and technologies that by defi- Although often well-intentioned and leads, a scientist may feel or actually nition have not already been proven. in some cases perhaps necessary, the be compelled to back away should Grant applicants are well aware of this paperwork required to study pathogens, these leads not fit into the mission or and stay away from “risky” projects in toxins, recombinant molecules, and type of work currently favored by an favor of “safe” projects. NIH intramural even panels of stored sera that have institute. scientists face the same problem. identification markers can become so
A related problem is the pressure to Although it is generally thought that onerous that investigators choose not conform that many tenured intramural intramural scientists have greater free- to do experiments in these areas. investigators experience when an in- dom to choose long-term “high-risk, The same applies to animal proto- coming institute director or scientific high- impact” projects, intramural scien- cols that now require so much infor- director wants to modify the scientific tists increasingly are choosing safer mation—well beyond the original in- direction of the institute. projects to ensure a good review by the tent of ensuring that the animals are Because decisions on the yearly bud- Board of Scientific Counselors. protected from undue pain and discom-
14 July — August 2006 fort—that approval often takes months and becomes a stifling paperwork ex- ercise. Recently Tenured The prohibition on outside consult- ing imposed on intramural scientists to avoid even the appearance of con- flict of interest creates still another Kevin Camphausen received his M.D. confined cancer. We developed an in problem. It diminishes interaction with degree from Georgetown University, vivo Lewis lung carcinoma (LLC) model the extramural community, limits sci- Washington, D.C., in 1996 and com- to evaluate urinary MMP-2 as a entific exchange, and reduces oppor- pleted a residency in radiation oncol- biomarker for disease recurrence after tunities to develop new technologies ogy at the Harvard Medical School Joint irradiation. and therapies. Center for Radiation Therapy, Boston, We were able to detect biologically Similarly, the restrictions on travel, where he studied the interaction of an- active MMP-2 as an early marker for lung lecturing, editing, and serving on sci- giogenesis inhibitors and radiotherapy metastases in C57B1/6 mice that had entific boards—together with the cum- in the Judah Folkman lab. He joined NCI been implanted with LLC and “cured” bersome paperwork required to ob- in 2001 as a tenure-track investigator with local irradiation. This rise in MMP- tain approval for some of these activi- and is currently chief of the Radiation 2 activity was then used as a signal to ties creates a negative environment — Oncology Branch. begin adjuvant angiostatin therapy, that makes interaction with the aca- Approximately 75 per- which successfully reduced demic extramural community more cent of the 1.2 million pa- the metastatic burden. difficult than ever before. tients diagnosed with non- With the knowledge that Although freedom of inquiry is not skin cancers in North urinary MMP-2 levels reflect and never has been totally open- America in 2007 will receive disease status in mice after ended—nor should it be—the corner- radiotherapy during the irradiation, we sought to ex- stone and success of the NIH intra- course of their disease. Im- plore this finding in radio- mural and extramural programs has proving the efficacy of ra- therapy patients using two been and remains bottom-up, investi- diotherapy would therefore biomarkers, MMP-2 and gator-initiated research. Anything that significantly contribute to VEGF (vascular endothelial erodes this freedom, no matter how the field of oncology. Christopher Wanjek growth factor). subtle, must be viewed with concern. Characterization of the Kevin Camphausen A pilot study (02-C-0064) Many of the issues discussed here processes regulating cellu- examining these two urinary have become so ingrained and ac- lar radiosensitivity has led to the hypoth- biomarkers was opened in early 2002. cepted that they are no longer readily esis that many of these cellular processes We recently published early findings recognized as the threats they truly are and signaling pathways can be targeted from this study. In samples obtained to freedom of inquiry. Restriction on for interruption, thereby predisposing tu- before radiotherapy, there were a greater freedom of inquiry will have an ad- mor cells to death. number of MMPs detectable in the urine verse effect not only on recruitment in laboratory and of patients with localized cancer than and retention of the current genera- The work my clinic focuses on two major projects: in that of normal controls (1.43 vs. 0.38). tion of scientists, but also on attract- of novel biomarkers of Similarly, patients with localized cancer ing the best of the next generations development early failure after radiotherapy, and his- had higher urinary levels than into science as a career. VEGF tone acetylation as a target for tumor- normal controls vs. 131.6 pg/mg How should the scientific commu- (317 cell radiosensitization. creatinine). Although the absolute val- nity deal with these and future prob- The first focus is the development of ues of these biomarkers were not able lems? Each issue is different and re- for re- to predict clinical outcome, comparisons quires a separate solution. Decisions a noninvasive biomarker tumor level the must be constantly weighed to find currence after irradiation. An early of the MMP or VEGF on last levels at the balance that provides the best en- marker of recurrence would allow pre- day of radiation with obtained patients follow-up predictive of vironment for creative endeavor. Open diction of which harbor sub- one-month were debate and constant appraisal and re- clinical disease and may benefit from disease status at one year. appraisal would seem to be the best additional therapy, instead of the cur- To validate the utility of these prom- approach. rent practice of delivering treatment to ising markers, patients with the same The NIH Assembly of Scientists pro- every patient at moderate risk of recur- histology undergoing a homogeneous vides a proactive venue for intramu- rence. treatment regimen needed to be stud- ral scientists to express concerns and Because tumor growth depends on ied. Therefore, we initiated a prospec- views. The AOS has worked success- angiogenesis, an increase in circulating tive Phase II study (04-C-0200) in pa- fully over the past couple of years with angiogenic factors could identify patients tients with glioblastoma multiforme the NIH administration on the prob- at risk for persistent or recurrent dis- (GBMs) undergoing radiotherapy to lems associated with the conflict-of- ease. Although angiogenic factors have determine whether these urinary interest regulations. Equal attention been explored as tumor markers, no biomarkers add to the Radiation Therapy and effort now should be placed on study has explored their utility as a tu- Oncology Group Recursive Partition these many other problems that im- mor marker across multiple tumor types Analysis, which uses clinical parameters pinge on scientific creativity so that or in patients receiving radiation. to divide patients into subgroups based the NIH IRP maintains its great and Matrix metalloproteinases (MMPs) on historical survival. This study should successful tradition of freedom of in- have been implicated in both primary be mature within the next year. quiry. and metastatic tumor formation. Marsha My second focus is the evaluation of —Abner Louis Notkins Moses and colleagues defined the pres- histone deacetylase inhibitors as radia- Chief, Experimental Medicine Section ence of biologically active MMP-2 or tion sensitizers. Histone acetylation plays Oral Infection and Immunity Branch MMP-9 in the urine of cancer patients a critical role in modulating chromatin NIDCR as an independent predictor of organ- structure and regulating gene expres-
15 — -
People Recently Tenured
sion. The balance of histone acetylation of RNA polymerase II and histone acetyltransferase is determined by the opposing actions transcription. (HAT) activity that is recruited of histone acetyltransferase (HAT) and These events must occur to promoters by activators. histone deacetylase (HDAC). in the presence of nucleo- However, we discovered that In addition to slowing tumor-cell pro- somes, in which DNA is SptlOp is in fact the activator coiled around a central of the histone genes, liferation, the HDAC inhibitors sodium which octamer of core histone pro- has butyrate and trichostatin A have also been sought after for teins. Nucleosontes are many years. been shown to enhance tumor-cell ra- compact structures capable SptlOp appears to be a rare diosensitivity. Their clinical utility, how- of blocking transcription at example of an activator with ever, is limited by their pharmacologic every step. To circumvent a sequence-specific DNA- characteristics. this chromatin block, eu- binding domain fused to a Although several HDAC inhibitors karyotic cells possess ATP- HAT domain. Our current aim have recently been developed that pos- dependent chromatin-re- is to place our observations sess favorable pharmacokinetic more modeling machines and histone-modi- in their biological context of cell-cycle and toxicity profiles, their ability to in- fying complexes. The former use ATP regulation of the histone genes. In ad- crease tumor-cell radiosensitivity cannot to alter nucleosome structure and to dition, we are investigating the implica- be assumed. We have been examining move nucleosomes along DNA. The lat- tions of the homology we have observed these HDAC inhibitors and have found ter contain enzymatic activities that between the DNA-binding domain of that several —including MS-275, CI-779, modify the histones to alter their DNA- SptlOp and the zinc-finger domain of depsipeptide, and valproic acid (VA) binding properties and to mark them for human foamy retrovirus integrase. indeed appear to enhance the radiosen- recognition by other complexes, which sitivity of tumor cells. have activating or repressive roles (the Frank DeLeo received his Ph.D. in mi- Because of its potential for clinical basis of the histone-code hypothesis). crobiology from Montana State Univer- application —oral bioavailability, a low The current excitement in the chro- sity, Bozeman, in 1996 and carried out toxicity profile, and penetration of the matin field reflects the realization that his postdoctoral training with William chromatin structure is of central impor- blood-brain barrier—we have conducted Nauseef at the University of Iowa, Iowa tance in gene regulation: The cell has further studies with VA. City, in the Department of Medicine. He dedicated complex systems to manipu- Our laboratory results suggest that VA- joined the staff at NIAID's Rocky Moun- late the repressive properties of chro- induced HDAC inhibition can lead to tain Laboratories (RML) in Hamilton, matin structure to maximum effect. Fur- an enhancement of radiosensitivity both Mont., in the fall of 2000 as a tenure thermore, multiple connections between in vitro and in vivo. Our data further track investigator in the Laboratory of chromatin and disease are apparent. suggest that continuous exposure to VA Human Bacterial Pathogenesis. He is We have developed a model system is necessary to achieve the maximum currently a senior investigator and chief to investigate the remodeling and his- the Pathogen-Host Cell Biology Section. enhancement. tone modifications that occur on gene of
Based on these findings, 1 initiated an My laboratory studies the interaction NCI Phase II trial (06-C-0112) testing this plasmid chromatin contain- of human polymorpho- nuclear leukocytes (PMNs, or agent as a radiation sensitizer in combi- ing a model gene in its tran- nation with temozolomide and radio- scriptionally active or inac- neutrophils) with pathogenic therapy in patients with newly diag- tive chromatin states from bacteria. Although most bac- nosed GBM. yeast cells and compare their teria are killed readily by structures. Our studies pro- neutrophils, pathogens such David Clark received his Ph.D. degree vide a detailed and surpris- as Staphylococcus aureus from the University of Cambridge, U.K., ing picture of the events oc- have evolved mechanisms to in 1986. He did his postdoctoral train- curring in the chromatin circumvent destruction by ing with Gary Felsenfeld at NIH. In 1995, structure on gene activation. these key innate immune he joined the Laboratory of Cellular and We discovered that induc- cells and thereby cause hu- Biology, as a ten- Developmental NlDDK, tion results in a remodeled man infections. Therefore, a ure-track investigator. In 2003, he chromatin domain that ex- better understanding of the moved to the Laboratory Molecular tends far beyond the promoter to in- of bacteria-neutrophil interface at the cell Growth Regulation, NICHD, where he is clude the entire gene. The formation of and molecular levels will provide infor- now a senior investigator and head of this domain requires the transcriptional mation critical to our understanding, the section on Chromatin and Gene activator and a remodeling machine. We treatment, and control of disease caused Regulation. propose that a highly dynamic chroma- by bacterial pathogens. The study of gene regulation is a pre- tin structure is created, facilitating ac- The Pathogen-Host Cell Biology Sec- requisite for understanding how cells cess to the DNA for initiation and elon- tion conducts a systematic molecular respond appropriately to a changing en- gation factors. Our current studies aim 1) dissection of steps involved in patho- vironment, how they implement devel- to increase our understanding of the opmental programs, and how a defect structure and dynamics of remodeled gen-host interaction, with specific em- in gene regulation can result in carcino- chromatin domains. ph asis on the interaction of bacterial genesis. Gene activation involves the In a second, related, project, we are pathogens with innate host defense recruitment of a set of factors to a pro- investigating the biological function of (neutrophils), and 2) research investi- moter in response to appropriate sig- the yeast SptlO protein, which we be- gating mechanisms mediating evasion nals, ultimately resulting in tne binding lieved initially to be a co-activator with of innate immunity by pathogens of 16 July-August 2007
special interest, such as methicillin-re- Aiyi Liu received his Ph.D. degree in sta- ondary parameter and showed the in- sistant S. aureus (MRSA). tistics in 1997 from the University of terval to have desired coverage prob-
During my first few years at RML, we Rochester, Rochester, N. Y. He was a ability. For a sequential phase II trial, I used genomics strategies to discover a postdoctoral research fellow at St. Jude’s obtained several efficient estimators to genetic program that links phagocyto- Children’s Research Hospital in Mem- reduce the bias in estimating a second- sis in human neutrophils with apoptosis. phis, Tenn., and an assistant professor ary probability. The methods can be This research redirected our thinking of biostatistics at Georgetown University used to obtain efficient estimation of the about neutrophil function in the innate Medical Center, Washington, D.C., be- toxicity rate when the response rate is immune response. fore joining NIH in 2002 as a tenure- the primary endpoint in a phase II can- Using similar genomics methodolo- track investigator in the Biometry and cer clinical trial. gies, we elucidated a global model of Mathematical Statistics Branch, Division Power and sample-size calculation are host cell-pathogen interaction, which is of Epidemiology, Statistics and Preven- integrated considerations in planning a broadly applicable to many bacterial tion Research (DESPR), NICHD. He is medical study. Unfortunately, such cal- pathogens. Collectively, these studies now a senior investigator in that branch. culation usually relies on correctly speci- lead to a new paradigm for the resolu- As an intramural investigator at NIH, fied values of nuisance parameters, that tion of human bacterial infections. I conduct independent statistical re- is, parameters that are not related to the Studies from our laboratory were also search and collaborate with investiga- treatment difference but need to be dealt among the first to identify complex ge- tors within and outside DESPR on de- with in the study. The study can be se- netic programs in bacteria that circum- sign, analysis, and interpretation and verely underpowered if the specification vent human innate immunity to promote publishing of biomedical is far from the truth. This situ- disease. This work, which comprises a studies. ation calls for sample-size re- series of studies, identified novel viru- Sequential methods is one calculation based on internal lence factors in human bacterial patho- of my major research areas. data. I investigated this issue gens. Sequential methods, which for a bivariate phase II can- Since late 2003, we have focused our allow a scientific hypothesis cer trial to evaluate toxicity research on the emerging problem of to be tested repeatedly at and response rate simulta- community-associated MRSA (CA- several time points using ac- neously, and also for stud-
MRSA), which is epidemic in the United cumulated data, are fre- ies comparing the accuracy States. CA-MRSA causes disease in oth- quently used in designing of two diagnostic medical erwise-healthy individuals, and these medical studies, particularly devices. I proposed several infections can be severe and/or fatal. clinical trials, because they approaches to re-estimating The molecular basis for the increased increase the ability to reduce the sample size to achieve incidence and severity of CA-MRSA dis- sample size and to terminate inferior the needed statistical power. ease is not known. treatments as early as possible. I have also been exploring statistical Work from our laboratory suggests that Independently or joined by other col- issues related to diagnostic devices (or enhanced CA-MRSA virulence is linked leagues, I have published a series of biomarkers), such as receiver operating to (or results from) evasion of killing by papers addressing various issues in the characteristic (ROC) curves analysis, neutrophils, which likely underlies the design and analysis of a sequential trial, which plots sensitivity and specificity. I ability of these pathogens to cause dis- with particular focus on statistical infer- found a linear function to combine sev- ease in otherwise-healthy individuals. ence upon termination of the trial. eral medical devices so that the sensi-
An S. aureus leukocyte toxin, Panton- It is well know that sequential sam- tivity of the resulting diagnosis is maxi-
Valentine leukocidin (PVL), is widely pling introduces bias to estimation of mized over a desired range of high speci- believed to be the cause of the increased treatment effect. 1 derived some explicit ficity. I also developed several sequen- severity and incidence of CA-MRSA in- formulas to evaluate the magnitude of tial methods to compare the diagnostic fections. However, our recent studies such bias and found that the bias can accuracy of medical devices. indicate PVL does not play a major role be substantially reduced using a simple Recently, I proposed and developed in CA-MRSA disease. This unexpected segmented estimation by shrinking the a two-stage testing procedure to evalu- finding will redirect the medical com- estimator toward zero for small treat- ate the measurement errors of an instru- munity toward other factors likely re- ment effect and subtracting a constant ment in measuring the level of disease- sponsible for CA-MRSA infections. for large treatment effect. For two-stage associated biomarkers. This procedure
Our efforts to understand MRSA patho- phase II trials, 1 discovered that the bias allows the investigator to assess the genicity are currently focused on iden- can also be substantially reduced by sim- measurement error at an early stage and tifying the proteins directly responsible ply subtracting an empirical estimator make decisions about whether more ex- for the type and severity of disease of the bias. periments are needed for further evalu- caused by these emerging human patho- Clinical trials are usually designed to ation. gens. test hypotheses for a primary endpoint. I am also interested in microarray data The long-term objective of this re- However, data on secondary endpoints analysis. In order to extract information search is to develop and/or promote de- are also collected and need to be ana- from a database with a large number of velopment of enhanced diagnostics, lyzed by taking into account the possi- genes and a relatively small number of better prophylactic agents, and new bility of early stopping of the trial. I de- samples, I found an efficient way to treatments for emerging infectious veloped a simple bias-corrected confi- perform principal components analysis pathogens such as CA-MRSA. dence interval for the mean of a sec- (PCA) via grouping genes into several 17 Recently Tenured
blocks according to their correlation. low-up for four cycles or until pregnancy Julie Segre received her Ph.D. degree Within each block, PCA is conducted occurs, whichever comes first. in genetics from the Massachusetts In- and important gene expression features Study volunteers will be followed stitute of Technology, Cambridge, in extracted. These selected features are throughout gestation, and pregnancy 1996, working with Eric Lander at the then combined for further PCA. This new outcomes will be recorded. Our main inception of the MIT Genome Center. She procedure, called “block principal com- outcome is spontaneous abortion, which was then a Damon Runyon-sponsored ponents analysis,” has the advantage of we hypothesize will be decreased in the postdoctoral fellow in the laboratory of computational simplicity and is as effi- aspirin arm compared with the placebo Elaine Fuchs at the University of Chi- cient as ordinary PCA. arm. Aspirin is a primary target of inter- cago, where she developed an interest I have now begun to examine several est because of its anti-inflammatory, in skin biology. In 2000, she was new research areas, including sequen- vasodilatory, and platelet-aggregation awarded a Burroughs -Wellcome Career tial and adaptive design methods for inhibition properties. We expect to be in Award in Biomedical Research and studies in diagnostic medicine, sequen- the field by July 1, 2007. joined NIH as a tenure-track investiga- tial ranking and selection of diagnostic The second epidemiological study is tor. She is currently a senior investiga- biomarkers, and a new model for sur- the BioCycle study, which is a longitu- tor and head of the Epithelial Biology vival and ordinal data. With the contin- dinal assessment of the effects of en- Section, Genetics and Molecular Biology ued excellent support of my branch chief dogenous hormones (that is, estrogen Branch, NHGRI. and division director, I look forward to and progesterone) on Combining classical ge- making more contributions to the sci- biomarkers of oxidative stress netics techniques and mod- ence of statistics. and antioxidant status during ern genomic tools, 1 study the menstrual cycle. gene-environment interac-
Enrique Schisterman received his Specifically, we measured tions at the skin surface. I Ph.D. in epidemiology from the State FiS-isoprostanes, TBARS study the formation of the University of New York at Buffalo in 1 999 (thiobarbiturate acid reactive skin barrier during develop- and completed his postdoctoral training substances), and total plasma ment, which is necessary to in epidemiological methods at the protein carbonyls as markers prevent the escape of mois- Harvard School of Public Health in the of oxidative stress; fat-soluble ture and the entry of infec- Department of Epidemiology. In 2002, antioxidant vitamins, water- tious agents. he came to NIH as a tenure-track inves- soluble vitamin C, and the The skin barrier is estab- tigator in the Division of Epidemiology, major antioxidant enzymes lished in utero at 32 weeks Statistics, and Prevention Research, were measured as markers of antioxi- (resulting in an incomplete barrier and
NICHD. He is currently a senior investi- dant defense. We assessed oxidative increased risk for dehydration and in- gator in the division. stress, hormones, and anti- fection in children born preterm—about My current research inter- oxidant levels at specific 2 percent). The skin barrier is maintained ests are twofold: 1) I have a times during the menstrual throughout life and reestablished after long-standing interest in re- cycle that represent the days trauma such as abrasion or wounding. productive and perinatal epi- with the greatest hormonal Even when the skin regrows, the en- demiology, and 2) I am work- variation. The study re- suing scar at the site of trauma contin- ing on developing analytical cruited and completed fol- ues to exhibit a mild barrier deficiency tools that are closely tied to low-up on 259 women, and compared to uninvolved skin for as etiological questions. In pur- we are now in the midst of along as one year. suit of the first interest, I am analyzing the data gathered. We modeled in animals the establish- in the midst of conducting In addition to these trials, ment of the skin barrier during devel- two studies. I have explored and am cur- opment and the interaction of the path- The Effects of Aspirin on rently exploring pooled- ways regulated by the transcription fac- Gestation and Reproduction (EAGeR) sample designs because they provide tors, KLF4, GATA-3, and the glucocorti- trial is a multisite, double-blind, placebo- practical and cost-effective solutions for coid receptor. controlled, randomized trial that will investigating oxidative stress as a me- We showed that mice with increased evaluate the effect of daily low-dose diator of reproductive outcomes. gap junctional communication exhibit aspirin on all phases of reproduction be- I am also involved in developing new mild barrier impairment under homeo- ginning at preconception and continu- methods for estimating the receiver op- static conditions. After wounding, an ing throughout pregnancy, including im- erating characteristic (ROC) curve and inability to restore the barrier arrested plantation and live births. the accompanying Youden index ac- the wounds in the hyperproliferative We plan to recruit 1,600 women pre- counting for measurement error, selec- state and resulted in immune cell infil- conception and actively follow them for tion bias, and information bias. tration. two menstrual cycles or until becoming Finally, I am interested in method- These studies suggest that the signal pregnant, whichever comes first. Active ological research focused on the assess- to restore the homeostatic balance be- follow-up entails collection of question- ment of biomarkers and exposure data, tween proliferation and differentiation naire data as well as regular specimen consideration of the limits of detection, after regrowth of the skin is restoration collection. Women who do not become statistical modeling of causal effects, and of the barrier and that, in its absence, pregnant within the first two cycles will design studies with pooled biospeci- the skin enters a pathologic state resem- remain in the study under passive fol- mens. bling psoriasis. 5 July-August 2007
I
II
Psoriasis is a common postnatal skin Swiss Institute for Experimental Cancer veal that what used to be considered disorder, affecting 2 percent of the popu- Research (Epalinges sur Lausanne, Swit- the defensive mechanisms of innate re- lation in the United States; its typical age zerland). From 1979 to 1999 he was at sistance and inflammation are indeed
of onset is in the third decade. Wound- Wistar Institute in Philadelphia and be- manifestations of tissue homeostasis and
ing is an initiating event in a significant came Hilary Koprowski Professor and control of cellular proliferation that have percentage of psoriatic patients and is Chairman of the Immunology Program; many pleiotropic effects on carcinogen- clinically referred to as the isormorphic he was also Wistar Professor of Medicine esis and tumor progression and dissemi- phenomenon. at the University of Pennsylvania in nation. Our future goal is to evaluate the hy- Philadelphia. He was director of the The interaction of the inflammatory pothesis that skin microbial diversity (a Schering Plough Laboratory for Immu- mediators and effector cells with carcino- mix, for instance, of bacteria, fungi, and nological Research in Dardilly, France, genesis and tumor1) progression is com- archae) plays a role in many common and an NIH Fogarty Scholar at the Labo- plicated and results in effects that either dermatological conditions, including ratory for Parasitic Diseases, NIAID, be- favor or impede tumor progression. atopic dermatitis (eczema). The onset fore becoming director of the Cancer In my own group and in collabora- of atopic dermatitis is typically within and Inflammation Program (CIP) and tion with the other CIP investigators,
the first year of life and affects about 1 chief of the Laboratory of Experimental research on the interface between in- percent of children in the United States. Lmmunology at NCL in Au- flammation, natural resis- More than half of patients with severe gust 2006. tance, and adaptive immu-
atopic dermatitis will progress to de- As CIP director, I oversee nity in the mouse and in hu- velop asthma and/or allergic rhinitis (hay the operations of two major mans will focus on: fever), disorders with significant mor- NCI intramural laboratories, The molecular and cel- bidity and mortality. the Laboratory of Experi- lular mechanisms regulating There are two classical explanations mental Immunology and the the activity of dendritic-cell for the role microbes play in skin dis- Laboratory of Molecular subsets, particularly the type
ease: 1) A specific microbe colonizes the Immunoregulation. I interferon-producing plas- skin to disrupt the balance of commen- These two laboratories macytoid dendritic cells, as sal microflora, and 2) microbes release constitute the major immu- well as conventional den- toxic substances or invade cells to in- nologic component of the Giorgio Trinchieri dritic cells, and their cross- duce an inflammatory response directly. CCR’s newly announced in- activating interaction with In fact, there are numerous possibili- flammation and cancer initiative, which other inflammatory cell types, NK cells, ties of how microbial communities con- spans the NCI’s campuses in Frederick and T cells tribute to human health and disease. and Bethesda and seeks to partner NCI’s 2) The role of plasmacytoid dendritic However, culture-dependent skin sam- expertise in inflammation and immunol- cells in the regulation of immune re- pling methods are incomplete assess- ogy with its cutting-edge cancer etiol- sponse and tolerance in experimental ments of microbial diversity and thus ogy and carcinogenesis program. models of cancer, autoimmunity, and are insufficient to fully address these My research interest has always fo- infections basic questions. cused on the interplay between inflam- 3) The molecular, structural, and sig- We propose to use novel genomic mation/innate resistance and adaptive naling aspects of receptors that recog- methods to sample skin microflora di- immunity and on the role of pro-inflam- nize pathogens— particularly Toll-like rectly and shed light on the above con- matory cytokines in the regulation of receptors, cytoplasmic NOD and RIG-
jectures in both normal and diseased hematopoiesis, innate resistance, and I — like receptors—and other surface re- dermatologic states. immunity. ceptors and their synergism or antago- We genomically classify the phylum My focus now is on the role of in- nism in the regulation of the inflamma- and genus of the bacteria by sequenc- flammation, innate resistance, and im- tory response ing the 16S rRNA genes directly from munity in carcinogenesis, cancer pro- 4) The immunosuppressive tumor skin biopsies and will characterize the gression, and prevention or destruction environment that results in alternate full bacterial genomes with of cancer. activation of macrophages and myeloid metagenomic sequencing. Recent studies are shedding a new cells and paralysis of dendritic cells, with The genetic program to specify, main- light on how innate resistance, as an in- an emphasis on the role of IL-10 and
tain, and heal the skin is complex. How- tegral part of inflammation, participates STAT3 activation
ever, the skin is an ideal system in which in oncogenesis and tumor surveillance. 5) Treatments aimed at reversing the to perform genetic and genomic experi- For a long time, innate resistance was immunosuppressive environment, com-
ments because it offers easy access to considered a primitive nonspecific form bined with others to activate innate re- diverse human skin disorders, excellent of resistance to infections that was sistance or modulation of the inflamma- animal models, and well-developed cell eclipsed by the potent and specific ac- tory response for antitumor therapy and organotypic culture systems. quired immunity of higher organisms. 6) Using genetic or chemical models
More recently, it has been recognized of colon and skin carcinogenesis to ex-
Giorgio Trinchieri received his medi- that innate resistance is not only the first plore the role of inflammation-related
cal degree from the University of Torino , line of defense against infections but also gene products, such as tumor necrosis Italy, in 1973. He was a member of the sets the stage and is necessary for the factor, IL-12, IL-23, IL-27, IL-10, IL-17, Basel Institute for Immunology (Basel, development of adaptive immunity. IL-22, Toll-like receptors and their sig- Switzerland) and an investigator at the Advances in cancer biology now re- naling molecules. S!
19 — The NIH Catalyst
Catalyst; All That Fizz
ummer’s here, and it’s a good time to take science outside. We’ll need S some small plastic bottles of carbonated water that you can buy in a Catalytic grocery store (how many and how large is up to you, but at least two Reactions? and the ones I used were 500 ml), at least three times as many large balloons, a cup of vinegar, a cup of baking soda, two clear cups, and a small nail. Combining baking soda and vinegar happens to make a great cleaner. vinegar f you have a photo or And smells a I other graphic that lot better than bleach, but just like bleach, you sure don’t want to get it in your eyes, so be reflects an aspect of life at careful. NIH (including laboratory Before you head outside, think about what we know about carbonated water already. It life) or a quotation that dances on the tongue, you can watch the bubbles rise in a glass, and if you drink it fast scientists might appreciate enough . . . well, the carbonation can come back in unexpected ways. But we’re going to do that would be fit to print in a bit more. the space to the right, why Fill one of your clear cups halfway with tap water and the other halfway with carbonated not send it to us via e- water, and place the two cups in the freezer. We ll come back to them later (but think about mail: [email protected]>; how the frozen results might be different). Now, outside we go. fax:402-4303; or mail: With a small nail, carefully perforate the cap of the carbonated-water bottle you just opened. Building 2, Room 2E26. About 15 holes will do. Stretch the balloon mouth across the top of the cap. This will be our receptacle for the gas that comes from the carbonated water, and preparing it ahead of time Also, welcome we allows us to catch as much as possible. “letters to the editor” for Mark the liquid level of the unopened bottle, and open it carefully. It will start to bubble publication and your immediately because the pressure has changed inside the bottle. When you safely have the reactions to anything on top off, screw on the other cap with the balloon attached to it. And shake! the Catalyst pages. It won’t take long to see the balloon expand, and if you shake the bottle enough, the balloon will become larger than the bottle itself. Lots of gas in there. But we can do more. Now let’s see what happens when we mix vinegar and baking soda. Place two tablespoons In Futu re Iss ues... of baking soda and one tablespoon of vinegar (easiest with a lunnel) into an empty bottle. Stand back (or you may find yourself covered in vinegary bubbles), get your balloon ready, Iron Regulation and repeat the same procedure. After you’ve cleaned up a bit, come back inside and look at the frozen water versus the ^ frozen carbonated water that you placed in the freezer about an hour ago. You’ll see a layer and Heart Attacks on top of the frozen carbonated water, but what is it? Thaw the glasses and note the water level, and also how fizzy the formerly frozen frothy water is. (Say that one quickly!) Nursing Research If you have any leftover bottles of carbonated water, freeze them (unopened), along with another bottle full of tap water. It won’t explode in the freezer, as cans can, because the bottle
is plastic, but after these two are frozen you will see just how much frozen water expands. Have fun with your carbonated water, see the mountain of bubbles created with vinegar and baking soda, and enjoy the warm weather! —Jennifer White
The NIH Catalyst is pub- Publisher Managing Editor Editorial Advisory Board lished bi-monthly for and by Michael Gottesman Fran Pollner David Davies, NIDDK the intramural scientists at Deputy Director Dale Graham, CIT NIH. Address correspon- for Intramural Research, OD Writer-Editor Elise Kohn, NCI dence to Building 2, Room Christopher Wanjek Susan Leitman, CC 2E26, NIH, Bethesda, MD Editors Director of Communications, OIR Bernard Moss, NIAID
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