N E W S A N D THE INSIGHT FROM THE STOWERS I N S T I T U T E FOR MEDICAL Stowers RESEARCH REPORT

FALL 2 0 0 Stowers Institute Principal Investigator Linheng Li (front right) and his research team unravel some of the mysteries of stem cell niches. 4 Front row from left: Wenjia Wang, Jeff Haug, Teri Johnson, Xi He. Back row from left: Jason Ross, David Scoville, Jiwang Zhang, Donna di Natale, Leanne Wiedemann.

Jim and Virginia Stowers believe basic research of the highest quality will Inside this issue . . . lead to practical solutions for human • Dr. Olivier Pourquié discovers a new and unexpected molecular mechanism disease. This important research is a long- to explain how vertebrae develop in embryos — one of many steps required to understand spinal cord deformities (Page 2). term process, and it may seem excruciat- ingly slow for those awaiting breakthrough • Dr. Linheng Li turns his groundbreaking analysis of stem cell niches toward treatments for presently incurable illnesses. an understanding of the pathogenesis of intestinal polyposis disease (Page 4). But it will, ultimately, point the way to • The Stowers Institute initiates new programs to benefit high school teachers better means of preserving health and pre- in the Kansas City area and college students across the country (Page 6). venting disease. Stowers Institute scientists V O L U M E 7 pursue the dream of Jim and Virginia • National and international leaders discuss their latest research at Stowers Institute symposia, and local scientists and students present their own findings Stowers by dedicating their professional (Page 8). lives to basic research. The results of their innovative research appear regularly in the • Stowers Institute investigators play prominent roles in the peer review process at world’s leading scientific journals. the NIH and as editors of peer-reviewed scientific journals (Page 10). A TOP TEN HIT: Olivier Pourquié Sheds Light on Mechanisms in Vertebrae Development

In the early 19th century, natural processes that orchestrate segmentation “New somites form in a defined scientists seeking to understand animal of vertebrae in chicks and mice has rhythm, implying an exquisite coordina- biology naturally turned to anatomy, stimulated increased interest in the field tion in the complex cellular movements and they observed a strikingly common while bringing him many recent honors. responsible for the embryo’s growth and feature: segmentation. Worms, insects, patterning,” Dr. Pourquié says. He calls and mammals all have repeating body A Segmentation Clock for this underlying temporal coordination the segments, a pattern that is particularly Somite Development “segmentation clock.” obvious in the human spine. Dr. Pourquié showed that the Vertebrae are generated early during Vertebrate embryos develop in a segmentation clock ticks according to embryogenesis, when body plans are being head-to-tail sequence, first forming varying expression of genes important in established. Malfunctions in this process anterior structures, like the head and fetal development. When the genes can result in severe spine deformities. neck, and then progressively adding flash on, a new, immature somite forms at the embryo’s tail end. Later, the same gene flashes again and another segment forms at the tail, elongating the head-to- tail axis. This oscillating gene expression is the molecular mechanism of the segmen- tation clock (Figure 2). Each oscillation of the segmentation clock produces one somite. As the tail elongates away from a somite, that somite begins to mature and progressively takes on more features of fully formed vertebrae. Dr. Pourquié and Postdoctoral Associate Julien Dubrulle discovered that Fibroblast Growth Factor 8 (FGF8) keeps the cells near the tail in an immature, undifferentiated state compatible with Associate Investigator Olivier Pourquié and his laboratory team take satisfaction in the accolades recently continued growth. bestowed on his segmentation clock research by the American Association of Anatomists, Nature’s Milestones in Development, and the Faculty of 1000 (Page 9). Over time, the concentration of the FGF8 signal dissipates and gradually Yet as obvious — and important — more posterior structures, such as the disappears as the tail elongates away from as the segmentation process is, very little trunk and tail (Figure 1). the somite, keeping it at a fixed distance attention has been paid to uncovering its The posterior part of the embryo from the tail. The temporal pattern of molecular mechanism. Dr. Pourquié, grows at the tail bud, where immature cells the segmentation clock creates a repetitive associate investigator at the Stowers proliferate and generate the body axis. As spatial pattern and coordinates the Institute, is changing that. His seminal it grows, the new tissue becomes segmented rhythmic generation of vertebrae. research in understanding the molecular into somites, or longitudinal sections.

2 The Stowers Report – Fall 2004 The Search for Answers Figure 1: Vertebrae derive from embryonic somites. This sequence As with most important discoveries, illustrates the head-to-tail vertebral development of a chicken. The two- this one raises new questions. First and day-old embryo (left) has 11 somites. foremost, how is the repetitive spatial The black lines indicate the position pattern created? Dr. Pourquié thinks he of those somites on the ten-day old has the answer. embryo (right) with a fully developed skeleton. The five most anterior Gene transcription produces multiple somites are incorporated into the skull copies of messenger RNA (mRNA) that (not shown on the right panel). are translated into an amino acid chain comprising FGF8. Because the FGF8 gene is transcribed, or turned on, only at the tail, and not further up in the somites, you would expect to find the mRNA only at the tail. But, Dr. Pourquié found evidence of FGF8’s mRNA further up the spatial gradient as well. “We believe it is mRNA degradation that drives the establishment of the gradient,” explained Dr. Pourquié. “As the mRNAs gradually degrades, the corresponding decrease in FGF8 protein concentration allows the somite to mature at a defined distance from the tail bud.” Dr. Pourquié currently is investigating what controls the number of segments in the body axis and how the number of Figure 2: The clock and the determination somites that will become cervical vertebra front model for somitogenesis. The deter- in the neck or thoracic vertebrae along mination front marks the level at which cells respond to the segmentation clock. It is defined the rib cage are determined in different by gradients of two signaling molecules (blue organisms. Long-necked animals such and red) that are mutually antagonistic: as one increases, the other decreases. As periodic sig- as swans may offer clues into these next Recent Papers phases of research, so Dr. Pourquié is nals from the segmentation clock reach the cells at the front, they begin to express specific genes seeking a suitable source of fertilized eggs Pourquié, O. (2003) The segmentation (black) that enable the cells to differentiate. clock: converting embryonic time into to incubate, which would allow him to This mechanism translates the temporal period- spatial pattern. Science, 301:328-330. study embryogenesis in swans. icity of the clock into the spatial periodicity of “This is an area of research that I the segments during extension of the body axis Dubrulle, J. , Pourquié, O. (2004) FGF8 (anterior section is at the top). find intriguing,” says Dr. Pourquié. “I am mRNA decay establishes a gradient that couples axial elongation to patterning in the looking forward to continuing the search vertebrate embryo. Nature, 427:419-422. for new answers to questions, and new questions to answer.”

The Stowers Report – Fall 2004 3 LINHENG LI: The Stop and Go Signals in Stem Cell Niches

Umbilical cord blood contains The Nurturing Niche “We want to get quantities suitable blood stem cells that, in the event of a for treatment in a clinical setting to serious disease, can sometimes be used to With collaborators at the Stowers determine if this work can be translated replenish the entire blood system without Institute and other institutions, Dr. Li into therapy for human blood diseases,” the need of a difficult bone marrow found the elusive niche for blood stem cells he says. Recently, they observed that transplant. This prospect offers comfort to in 2003* (2003 Annual Report). His isolated osteoblast cells form a niche-like some new parents who choose to save findings resolved a quarter-century search structure in a tissue culture dish (Figure 1). umbilical cord blood to protect their by demonstrating how certain osteoblast “However, the primary osteoblasts children against future health risks. But cells in the bone’s interior lining form tend to either differentiate or undergo even this novel procedure is no guarantee. miniature caves where the marrow’s stem apoptosis and die after a short time in “Unfortunately, only about five to cells nestle. They also demonstrated that culture,” he says. “Now we’re focusing 10 milliliters of cord blood can be saved, expanding the population of osteoblast on isolating osteoblastic niche cells using and that quantity does not really contain niche cells caused a parallel increase in flow cytometry and further establishing a great many stem cells,” explains hematopoietic stem cells in the bone marrow. them as cell lines. This would allow us Stowers Institute Assistant Investigator Dr. Li’s lab is now working on to investigate the molecular mechanism Linheng Li. “Furthermore, scientists still reconstituting the niche in the laboratory and genetic pathways that regulate stem have difficulty getting stem cells to to create an incubator for expanding the cell development and self-renewal in the multiply into the quantities such therapies stem cell population. bone marrow.” might require.” Dr. Li is examining alternative solutions to this and other problems of human health in his laboratory. His research focuses on the physical surrounding, or niche, that houses stem cells in the body and helps regulate their growth. Dr. Li is especially interested in what happens to stem cells when they are removed from their niche. Outside of their niche, these cells no longer proliferate readily, and this can cause problems for therapeutic bone marrow transplantation. Additionally, he is interested in understanding how abnormal signaling in the intestinal stem cell niche can cause too much stem cell growth and lead to polyposis disease and colon cancer — a leading cause of death Linheng Li; Jeff Haug, managing director of the Cytometry Facility; and Sach Jayasinghe, cytometry in the western world. research technician II, work together in the Cytometry Facility.

4 The Stowers Report – Fall 2004 Ultimate Goal: Regenerating encourages too much cell growth in the further study the intestinal stem cells. Intestines intestinal lining. To explore an individual “With this award, we can undertake gene’s role in a complex system, scientists additional experiments that might lead In defining the bone marrow stem often “knock out” or disable the gene and to something very important,” he says. cell niche, the Li lab identified a signaling observe the effect in a model organism. “The ultimate goal of studying and gene, bone morphogenetic protein (BMP), To that end, Dr. Li’s lab performed genetic characterizing the intestinal stem cells that inhibits stem cell proliferation. They manipulation to block BMP signaling in is to be able to regenerate the intestine determined that silencing the BMP signal mice. As expected, the mutant mice and to develop potential treatments at the niche increased the stem cell developed intestinal polyposis, mimicking for colon cancer, ulcers, or other intest- population, and it seems that this holds human juvenile polyposis. inal diseases.” true for other niches as well. Dr. Li’s results, reported in the “It now appears that BMP’s regulation October issue of Nature Genetics**, of the stem cell number is not limited found that BMP’s signal specifically to the hematopoietic system, but also is inhibits signaling of the Wnt gene. The seen in the intestinal system,” Dr. Li says. Wnt pathway promotes intestinal self- In a variety of intestinal diseases, renewal by sending an adhesive-like abnormal growths called polyps form protein, b-catenin, into the stem cell Stem cells nestle among on the mucous lining and cause obstruc- nucleus, triggering stem cell division. hematopoetic cells along the tion — a process partially attributed to Essentially, the Wnt “go” signal competes arch of an osteoblast. runaway activity of stem cell populations. with the BMP’s “stop” signal, while PTEN To investigate the underlying molecular mediates their struggle like a police Figure 1: Image of osteoblast niche for hematopoeitic stem cells forming in lab officer making sure traffic runs smoothly. mechanism, the lab analyzed intestinal culture. Certain osteoblasts elongate, forming a stem cells in mutant mice lacking the When the BMP function is lost, Wnt smooth arch on one edge and a jagged shape, like BMP signal. increases and escapes PTEN’s regulation. a bone cavity, on the other edge. The stem cells “The intestines exercise a controlled “We detected duplicated stem cells nestle in the arch. balance between the genetic pathways in the polyp region,” Dr. Li observes. Recent Papers that stimulate stem cell proliferation and This indicates that the unchecked Wnt those that inhibit it,” Dr. Li explains. signal increases self-renewal of stem cells. * Zhang, J. , Niu, C. , Ye, L. , Huang, “This balance ensures that the niche Presumably, the overproduction of stem H. , He, X. , Tong, W. G. , Ross, J. , Haug, produces neither too many nor too few cells sets off a frenzy of cell division that J. , Johnson, T. , Feng, J. Q. , Harris, S. , Wiedemann, L. M. , Mishina, Y. and Li, L. stem cells.” leads to the growth of a polyp. (2003). “Identification of the haematopoietic Significantly, three diseases — “In this work we have identified stem cell niche and control of the niche juvenile polyposis syndrome (JPS), biological markers to recognize intestinal size.” Nature, 425(6960): 836-41. juvenile intestinal polyposis, and stem cells,” says Dr. Li. “We showed the ** He, X. C. , Zhang, J. , Tong, W. G. , Cowden’s disease — have been linked to signaling components of the BMP, Tawfik, O. , Ross, J. , Scoville, D. H. , Tian, mutations in signaling genes (BMPR1A, PTEN, and Wnt pathways at the level Q. , Zeng, X. , He, X. , Wiedemann, L. M., SMAD4, and PTEN, respectively). of single stem cells in a complicated Mishina, Y. and Li, L. (2004) BMP signaling Since BMP and PTEN (a tumor mammalian system.” inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin suppressor) normally inhibit intestinal Dr. Li recently was awarded the second signaling. Nature Genetics, 36, 1117-1121. stem cell division, Dr. Li hypothesized that annual Hudson Prize (page 9) and plans Commentary 1038-39. these genes malfunction in a way that to use the grant money to isolate and

The Stowers Report – Fall 2004 5 Reaching Out to the Region

Science Teachers Access to Stowers Scholars Program Research at Stowers (STARS) For college students who are studying When Abby Freeman arrived at the science, Ms. Freeman administers a summer Stowers Institute in November 2003 as internship program. The Stowers Scholars vice president for administration, she began Program encourages students to consider working on a way for Kansas City teachers graduate studies in basic research and careers to benefit from the Institute’s extraordinary as research scientists. research. Ms. Freeman had participated in a “Impressionable college sophomores similar program at the University of Texas and juniors see what it is like to do basic Southwestern Medical Center in Dallas, research under the mentorship of a principal Abby Freeman works with Stowers Scholars. so she understands that developing future investigator in a top-notch lab where people Applications for the 2005 Stowers Scholars researchers depends on good high school love what they do,” explains Ms. Freeman. Program are due by Feb. 4, 2005. For more science teachers getting their students In 2004, 80 students applied and 8 were information visit Training Programs at excited about science. That is why Ms. accepted to an intensive 8-week experience www.stowers-institute.org. Freeman coordinated the launch of the in a research lab. STARS program this November. “We did not want to duplicate what Stowers Scholars 2004 Projects already existed here,” she says of programs sponsored by the Kansas City Star and by Student Scholar School and Project Science City at Union Station that target all students and provide supplemental Brian Chase Massachusetts Institute of Technology Ting Xie Lab “Identification of Genes for Germline Stem Cell Self-Renewal materials and classroom kits for any inter- in the Drosophila Ovary by Overexpression Screens” ested teacher. “We wanted to add a missing layer of outreach to the area schools while Laura Hughes Northwestern University remaining within Stowers’ capabilities and Chunying Du Lab “Identification of Caspase-2 Substrates” purposes. As a research institution, we can- not provide hands-on lessons, but we can Jessica Leonardi Texas A&M University share access to the exciting new discoveries Peter Baumann Lab “Mapping the Essential Domain of Pot1” in biomedical research that secondary sci- ence teachers may not otherwise have. Kathleen Lindstrom University of Kansas “When the participating teachers Scott Hawley Lab “A Germline Clone Screen to Identify Genes Involved in Meiosis” become excited and invigorated about sci- ence, they can encourage students to study Erin Miller Kansas State University science in college,” she says. “We believe Jennifer Gerton Lab “Deletion Mutagenesis of Budding Yeast MND1” programs like STARS can ultimately increase the number of science students in Alyse Prince Carnegie Mellon University Susan Abmayr Lab “Analysis of Defects in Muscle Development Through the colleges and universities.” Generation of Mutations in the sns and Blow Genes”

Lauren Sisel University of Missouri-Rolla Paul Kulesa Lab “Multicolor Labeling and Time-lapse Imaging of Neuronal Precursor Cells in Living Chick Embryos”

Erin Smith Truman State University Jerry Workman Lab “Cloning and Expression of Novel dAda1 Protein”

6 The Stowers Report – Fall 2004 BioMed Valley yield a growing stream of income in support A Second Home for Research of more basic research. The arduous process of advancing “I am unaware of any other such With the growing vision of BioMed discoveries out of basic research labs into model,” says Richard W. Brown, co-chair of Valley comes an imminent need for more the hands of physicians who treat patients the board of the Stowers Institute as well as research space. Bill Neaves, president and can take a decade or more. Even before the chair of the boards of both BVC and BVD. CEO of the Stowers Institute, explains Stowers Institute opened its research facility “We want to elevate the quality of research that at the rate the Institute is attracting in Kansas City, Jim and Virginia Stowers in the region, and that will, in turn, attract investigators, a second facility of equal size to wanted to do everything possible to ensure more high-quality scientists and students to the first will be required by the end of the that research conducted here would benefit the partnership institutions.” decade. In preparation, Mr. and Mrs. Stowers people as quickly as possible. They also want- “Virginia and I have been gratified to announced earlier this year that they were ed to see the Institute boost the economy of witness the efforts of our government leaders committed to the expansion and were the Kansas City area — a geographic region in Kansas and Missouri to support growth of appointing an architect to integrate the new that Jim and Virginia call BioMed Valley. excellent life science at both state universi- facility with the original. At the top of the Now, they have announced an innovative ties,” says James E. Stowers Jr., co-founder of scientists’ request list for the expansion: way to fulfill both goals through the creation the Stowers Institute. “If we all pull together creative design of common spaces to promote of the BioMed Valley Partnership. to achieve the BioMed Valley dream, Kansas the social interactions that can lead to new This non-profit organization, incor- City can become the best place anywhere for ideas and collaborations — a hallmark of porated as BioMed Valley Corporation life science research and for turning discover- the current facility. (BVC), will directly support researchers ies from that research into products that can at the University of Missouri-Kansas City, help people everywhere.” the University of Kansas, and the Stowers Institute. BVC’s wholly-owned subsidiary, BioMed Valley Discoveries (BVD), will assist these three partner institutions with technol- ogy development and commercialization. The proceeds will be shared equally with the inventors and their institutions. Scientists will be directly compensated for their work, and the profits garnered by the institutions will reside in an endowment at BVC to (From left to right) Bill Neaves, Dick Brown, Virginia Stowers, Jim Stowers, and David Welte work together to help BioMed Valley achieve its full potential.

Mike Washburn, director of Proteomics, and Paul Kulesa, director of Ting Xie, Susan Abmayr, Chunying Du, and Arcady Mushegian the Imaging Center, discuss their work in their shared library area. meet in the cafeteria to discuss a current research challenge.

The Stowers Report – Fall 2004 7 GOING TO KANSAS CITY: Conferences at the Stowers Institute

Paul Trainor organized the 44th Annual Midwest Regional Developmental Biology Meeting and Singer Symposium with co-chairs Drs. Krumlauf and Pourquié. This was the second year that the Stowers Institute hosted the meeting. A distinguished roster of speakers discussed the latest research on spinal cord development, stem cells, embryonic development, and congenital abnormalities. The meeting provided young postdoctoral fellows and graduate student researchers with a forum for presenting and discussing their own work and mingling with national and international research leaders. Dr. Trainor also co-chaired a sym- posium on stem cell science with Ken Scott Hawley, Jennifer Gerton, and Peter Baumann worked together to coordinate the “Structural Peterson of the University of Kansas Biology of Chromosomes” conference. Medical Center on September 27. Plenary Together with Assistant Investigators Genome: New Tools and Concepts.” At a speakers were Mario Capecchi of the Jennifer Gerton and Peter Baumann, previous workshop in Cambridge (UK) in University of Utah, who pioneered many Investigator Scott Hawley organized the early 2003, Drs. Pourquié and Burt estab- of the techniques used in stem cell conference “Structural Biology of lished the International Chicken Genome research, and David Scadden of Harvard Chromosomes” on April 22 and 23. The Consortium, the first coordinated effort Medical School, who helped define the sessions presented exciting insights into directed at sequencing an avian genome. location of hematopoietic stem cells in how changes in the structure of chromo- Presenters discussed the status of the the bone marrow. somes support their proper function chicken genome project, its place in the “This symposium served as a catalyst throughout the life of the organism. broader context of genome evolution, for the scientific community in Kansas The conference offered an innovative and newly developed research tools. and Missouri to meet regularly to exchange twist on traditional scientific networking. Participants learned that the relatively ideas and techniques advancing the Each of the seven invited speakers small chicken genome has many fewer understanding of stem cell science and its brought along a graduate student and a repeat sequences than the human genome possible applications,” says Dr. Trainor. postdoctoral fellow to meet with their and has undergone less “shuffling” than counterparts at the Stowers Institute in rodents and fish, suggesting that it may be small workshops. closer to ancestral vertebrate chromosomes. “They had the opportunity to form “The meeting helped shape the links between labs with researchers at levels realization that the chick will be a similar to their own, who do the work at the powerful experimental model species for bench on a daily basis,” explains Dr. Hawley. researchers working with other systems,” “We’ve had great feedback that tells us says Scientific Director Robb Krumlauf. this was a wonderful investment of effort.” “The Chicken Genome: New Tools From April 30 – May 2, Associate and Concepts” was reviewed in several Paul Trainor organized the 44th Annual Midwest Investigator Olivier Pourquié and Dave journals, including Developmental Cell Regional Developmental Biology Meeting and Burt of the Roslin Institute co-chaired and Developmental Dynamics. Singer Symposium, which was co-chaired by two a conference entitled “The Chicken On June 5-8, Assistant Investigator Stowers Institute colleagues.

8 The Stowers Report – Fall 2004 Awards and Distinctions

Associate Investigator Olivier Pourquié’s paper in the Two Nature Milestone Researchers January 29, 2004 issue of Nature attracted attention as a landmark Now at Stowers contribution towards understanding vertebrate development. The editors called his findings on the role of mRNA decay in the Nature’s Milestones in Development series segmentation process (pages 2-3) “an entirely new and unexpected highlights significant research discoveries in develop- mechanism for forming morphogenetic gradients.” The Faculty of mental biology over the past 100 years. A group of 34 1000, an organization that screens the thousands of weekly journal developmental biologists helped select 24 milestone articles to highlight the few most important, ranked Dr. Pourquié’s achievements that revealed fundamental developmental article at the top of the ten most significant recently published mechanisms conserved across the animal kingdom. papers in all biology by early March. Meanwhile, Nature credited The most recent addition to the series, Milestone 24, the most recent of their 24 “Milestones in Development” (right) highlights Dr. Pourquié’s work on somitogenesis and to Dr. Pourquié’s discovery of the segmentation clock. He was molecular clocks completed at the Developmental also awarded the 2004 Harland Winfield Mossman Award in Biology Institute of Marseille, France. An earlier Developmental Biology from the American Association of Milestone, no. 11, credits the contribution of Dr. Rob Anatomists (AAA). Dr. Pourquié holds a NIH R01 grant and Krumlauf, scientific director, when he worked at the serves on a NIH Study Section (Page 10). National Institute for Medical Research in England, Assistant Investigator Linheng Li received the 2004 Hudson where he discovered that mouse and fly Hox genes Prize for his discovery of the hematopoetic stem cell niche. M.R. have similar spatial and functional organization. Hudson, the founder of Hudson Oil Co. and later Fisca Oil Co., established the Texas-based Hudson Foundation in 1991 to further his lifelong interest in supporting education, medical research, children’s issues, and the arts. The foundation established programs at the University of Texas Southwestern Medical Center in Dallas and the Stowers Institute to recognize outstanding young scientists who have made important discoveries. Associate Investigator Ting Xie received the inaugural prize in 2003 for defining the stem cell niche in Drosophila ovaries. “The $50,000 stipend will enable Dr. Li to pursue his exciting work on stem cells more aggressively,” says Bill Neaves, president and CEO of the Stowers Institute. Assistant Investigator Paul Trainor received a five-year grant from the National Institutes of Health (NIH) to study how neural crest cells contribute to the formation of the head and face during mammalian embryonic development. Head and facial abnormalities Milestone #11: Homeotic Genes and Colinearity constitute one of the largest groups of congenital birth defects. http://www.nature.com/milestones/development/milestones/full/ One focus of Dr. Trainor’s lab is Treacher Collins syndrome, which milestone11.html develops very early during pregnancy and encompasses cleft palate, Milestone #24: Somitogenesis and Molecular Clock problems with jaw formation, and ear and hearing defects. http://www.nature.com/milestones/development/milestones/full/ milestone24.html Investigator Ron Conaway’s NIH MERIT grant was renewed for another five years. This category of grant is reserved for investigators who are highly productive and well established leaders in their field of study. Dr. Conaway investigates the role of RNA polymerase in gene transcription.

The Stowers Report – Fall 2004 9 Extracurricular Activities

Investigators at the Stowers Institute for Medical Research do not spend all of their time in their labs and classrooms. Many also contribute time to reviewing the work of their colleagues on behalf of the National Institutes of Health (NIH) and various scientific journals. “You learn in science that there are lots of service roles,” explains Scientific Director Robb Krumlauf, “whether it’s hosting a meeting to educate scientists, reviewing journal articles, or participating in the grant review process.”

Judging Grants

The NIH funds the largest portion of research in the United States. To ensure that these grants promote the best and Robb Krumlauf, Jerry Workman, Ron Conaway, and Olivier Pourquié each serve as reviewers of requests for funding from the NIH and other organizations. most beneficial research, the NIH con- venes Study Sections for each field of research and charges them with reviewing trated effort to review the grant proposals Reviewers. This board evaluates research and evaluating the merits of grant propos- before attending a two-day meeting at done in the laboratories supported by als in that field. NIH headquarters in Bethesda, Maryland,” the National Cancer Institute and recom- “Study Sections are the heart of the says Dr. Krumlauf. mends funding levels for those labs. peer-review process. They sustain the Each of the 16 or so members of a commitment of the NIH to fund only Study Section is responsible for presenting Reviewing Papers meritorious research,” explains President detailed reviews of approximately 10 grant and CEO Bill Neaves. “I’m proud of the proposals at each of three meetings during Another integral part of the peer- Institute’s high level of participation in the year. All members listen to these review process entails rigorous evaluation the NIH peer-review process.” reviews and then vote priority scores that of scientific papers for publication in jour- Dr. Krumlauf serves as a member and determine which grants get funded. nals. Every Stowers investigator has been co-chair of one of the two Study Sections “This participation benefits on the “reviewed” end, but several also devoted to developmental biology (Dev2), investigators at the Stowers Institute,” have prominent roles on the editorial while Associate Investigator Olivier Dr. Neaves adds, “because Study Section boards of leading journals. Pourquié is a member of the other major members can provide insightful guidance Drs. Krumlauf and Pourquié both study section reviewing grants in develop- to their colleagues about the evaluation serve as editors of Developmental Biology, mental biology (Dev1). Investigator Ron process and how to structure grant and Drs. Ron Conaway and Joan Conaway Conaway belongs to a Study Section deal- proposals to meet the strict review belong to the editorial board of the Journal ing with molecular biology. standards of the NIH.” of Biological Chemistry. Dr. Workman is a “It’s important for the Stowers Recently, Investigator Jerry Workman member of the Board of Reviewing Editors Institute to participate, but it is an onerous accepted an appointment to the National of the journal Science and is an editor for effort, requiring one full week of concen- Cancer Institute’s Board of Scientific Molecular and Cellular Biology.

10 The Stowers Report – Fall 2004 A TOP TEN HIT: Olivier Pourquié Sheds Light on Mechanisms in Vertebrae Development

In their roles as editors, the Stowers investigators receive manuscripts for their In the early 19th century, natural processes that orchestrate segmentation “New somites form in a defined respective journals, assign reviewers, and scientists seeking to understand animal of vertebrae in chicks and mice has rhythm, implying an exquisite coordina- evaluate the critical reports to reach a final biology naturally turned to anatomy, stimulated increased interest in the field tion in the complex cellular movements decision on acceptability for publication. and they observed a strikingly common while bringing him many recent honors. responsible for the embryo’s growth and “Science receives ten times more feature: segmentation. Worms, insects, patterning,” Dr. Pourquié says. He calls papers to review than they can publish,” and mammals all have repeating body A Segmentation Clock for this underlying temporal coordination the Dr. Workman explains. “The editors are segments, a pattern that is particularly Somite Development “segmentation clock.” not professional research scientists, so obvious in the human spine. Dr. Pourquié showed that the they assemble a board of reviewing editors Vertebrae are generated early during Vertebrate embryos develop in a segmentation clock ticks according to who are experts in their research fields. embryogenesis, when body plans are being head-to-tail sequence, first forming varying expression of genes important in We receive PDF files of submitted papers established. Malfunctions in this process anterior structures, like the head and fetal development. When the genes and must review them within 48 hours. can result in severe spine deformities. neck, and then progressively adding flash on, a new, immature somite forms We read to see if a paper looks like a solid at the embryo’s tail end. Later, the same piece of research that will have high gene flashes again and another segment impact, and we write a review paragraph that ranks it and recommends whether it forms at the tail, elongating the head-to- should be reviewed in depth.” tail axis. Another duty for Dr. Workman is This oscillating gene expression is to recruit important papers to Science Joan and Ron Conaway are members of the editorial board of the Journal of Biological Chemistry. the molecular mechanism of the segmen- rather than competing journals. “I keep tation clock (Figure 2). Each oscillation my eyes open at meetings for something of the segmentation clock produces one interesting that is still unpublished somite. As the tail elongates away from a and recommend that the investigators somite, that somite begins to mature and consider publishing it in Science,” progressively takes on more features of he explains. fully formed vertebrae. Dr. Workman says that while Science Dr. Pourquié and Postdoctoral is looking for something “hot and sexy,” Associate Julien Dubrulle discovered that Molecular and Cellular Biology is more Fibroblast Growth Factor 8 (FGF8) keeps of a “workhorse” journal where a larger the cells near the tail in an immature, portion of scientific material is published. undifferentiated state compatible with As an editor, he decides if a paper is worthy Associate Investigator Olivier Pourquié and his laboratory team take satisfaction in the accolades recently continued growth. of review. If so, he sends the paper to three bestowed on his segmentation clock research by the American Association of Anatomists, Nature’s Milestones in Development, and the Faculty of 1000 (Page 9). Over time, the concentration of reviewers who may provide a list of problems the FGF8 signal dissipates and gradually for the researchers to resolve. Yet as obvious — and important — more posterior structures, such as the disappears as the tail elongates away from “It’s a good process because the addi- as the segmentation process is, very little trunk and tail (Figure 1). the somite, keeping it at a fixed distance tional experiments improve the quality of attention has been paid to uncovering its The posterior part of the embryo from the tail. The temporal pattern of the published data,” he says. “This is espe- molecular mechanism. Dr. Pourquié, grows at the tail bud, where immature cells the segmentation clock creates a repetitive cially good for junior scientists. And some- associate investigator at the Stowers proliferate and generate the body axis. As spatial pattern and coordinates the times additional experiments completely Jerry Workman dedicates time to his duties as a member of the Board of Reviewing Editors for the Institute, is changing that. His seminal it grows, the new tissue becomes segmented rhythmic generation of vertebrae. change the interpretations of results.” journal Science and as an editor for Molecular and Cellular Biology. research in understanding the molecular into somites, or longitudinal sections.

2 The Stowers Report – Fall 2004 The Stowers Report – Fall 2004 11 ® The Stowers Report Hope Shares Vol. VII Published by the Between January 1 and October 7, 2004, contributions of at least $1,000, the minimum for Stowers Institute for establishing a Hope Shares® account in the endowment of the Stowers Institute, Medical Research were received from, or in memory of, the following: 1000 E. 50th Street Kansas City, Missouri 64110 $100,000 or MORE $1,000 or MORE Tel: (816) 926-4000 Fax: (816) 926 2000 Dunn Family Foundation* Sierra Aviation - www.stowers-institute.org American Century Companies $25,000 or MORE Robert and Lynette Jackson Tom and Nancy Juda Foundation Dawn Lind CONTRIBUTORS: William and Peggy Lyons Photos: $5,000 or MORE Tom and Jeanne Olofson Don Ipock Craig and Maryanne Roepke Isaac J. and Rena Jonathan Science Writing: Darrell and Marjorie Spaedy William B. and Priscilla W. Neaves Cathryn Delude Rick and Betsey Solberg Dennis and Sally von Waaden John and Shirley Wagner Design and Layout: Kuhn & Wittenborn Advertising In Memory Of Austin E. and Laura Wilson Helen I. Lebens

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These donors and those they honor will never be forgotten. Every attempt has been made to ensure the accuracy of the above list. In case of error or omission, the Stowers Institute wishes to be advised.

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