October 25 – 27, 2002
                                                  Arizona Cancer Center, University of Arizona
Reflections by  Sarah Ziegler

For all who believe that dreams can’t come true, I can tell you that for three days in October, I had the wonderful experience of
seeing my dreams become reality.

Meanwhile, my continuing reading of newly published studies found a link between MHE and Heparan Sulfate. I subsequently
found researcher Dr. Jeffrey Esko and I contacted him.  He was doing research on Heparan Sulfate and signaling between
genes, and while he had heard of the possible link with MHE, he had no idea of what MHE actually entailed. When I explained to
him about the disease, he became very interested in applying his knowledge to MHE research. I put
Dr. Esko in contact with Dr. Hecht, who provided him with samples for his start into MHE research, thus establishing the
beginning of a network of MHE researchers and establishing the link between Heparan Sulfate and MHE.  Subsequently, Dr. Esko
started his own research project, collecting samples through the National MHE Research Registry.

One of my next contacts was with Dr. Dan Wells of the Department of Biology and Biochemistry,  University of Houston, an
expert in understanding the molecular basis of human genetic diseases present on chromosome 8, and one of the researchers
who did much of the preliminary work on EXT 1.  Not only was Dr. Wells receptive to my initial phone call, he has become a
steadfast teacher, always willing to translate the language of science into something I can understand.  

My Internet searches next led me to Dr. Scott Selleck, who was then Associate Professor of Molecular & Cellular Biology and
Director of the Program in Molecular Genetics, Arizona Cancer Center, who was working on growth factor signaling, cell division
regulation and control of tumor growth, utilizing fruitfly models (Drosophila melanogaster).  The findings of Dr. Selleck and his
team suggest the possibility that changes in the levels of heparan sulfate in patients with MHE could alter the distributions of
secreted growth factors at the growth plate.  

During my numerous conversations with these and other researchers,
I kept hearing that they wished for a forum where they could all sit down together and share ideas, findings, etc.  I approached
Dr. Selleck and Dr. Esko with the idea of the first international MHE conference, a conference that would be the first of its kind:
a multi-disciplinary working conference involving scientists involved in various aspects of MHE research, as well as orthopaedic
surgeons and representatives of the MHE Community, who would enlighten the attending scientists about the realities of this

After much discussion, planning, and work, the First International MHE Conference was held at the Arizona Cancer Center from
October 25 to 27, 2002.  I would like to gratefully acknowledge the support of the sponsors of this groundbreaking conference:
The Molecular Genetics Program of the Arizona Cancer Center, The Mizutani Foundation for Glycoscience, The Orthopaedic
Research Society, Pfizer, Purdue Pharma, The National Institutes of Health, and The Arizona Cancer Center.  

My journey began on October 23rd, when I flew to Houston to meet with Dr. Hecht. This was the first researcher that I actually
had the opportunity to put a face to, after three years of telephone calls and emails.   
Dr. Hecht was a gracious host, taking me on a tour of her laboratory, and showing me what happened with the MHE samples
once they were received at the lab. Dr. Hecht and I flew on to Arizona together.

As this was a scientific conference, much of what was discussed was in scientific terms which are, at best, difficult to
understand, and impossible for me to explain.  Some of the conference speakers have graciously offered to write about their
research or their reactions to the conference for a special edition Newsletter to be published at a later date.   The following is a
description of the participants and subjects covered during the three-day conference.

Michael J. Goldberg, M.D., Chairman of the Department of Orthopaedics at Tufts University School of Medicine and George H.
Thompsom, M.D., Professor of Orthopaedic Surgery and Pediatrics, Case Western Reserve University and Director of Pediatric
Orthopaedics at Rainbow Babies & Children’s Hospital, discussed Clinical Presentation and Treatment of MHE.

This was followed by presentations on Medical Genetics.  Wim Wuyts of the University of Antwerp discussed “Hereditary Multiple
Exostoses, a genetic overview.” One of the goals of research is to be able to apply what is learned in the lab to clinical
applications.  This has now happened with one important aspect of MHE research.  Two labs now offer EXT 1 and EXT 2 gene
analysis:  Dr. Wuyts laboratory at the Department of Medical Genetics, University of Antwerp (Belgium), and GeneDX, Inc. in
the United States. These labs use direct sequencing technology, which is the gold standard for mutation detection.  

Gregory Schmale spoke on “Mutations in the EXT 1 and EXT 2 genes” (Gregory A. Schmale, MD, Wendy H. Raskind, MD,
University of Washington, Seattle).  Christine Alvarez then spoke about “Geneotype Phenotype Correlation in Hereditary Multiple
Exostoses” (C.M. Alvarez, S.J. Tredwell, M.R. Hayden, British Columbia Children’s Hospital).

In the Workshop, An Introduction to Therapeutic Strategies, Jeffrey Mai of the University of Pittsburgh School of Medicine spoke
about “Gene transfer & protein transduction approaches for therapy,” gene transfer approaches for treating other diseases that
may one day have relevance to gene therapy for MHE.   

During the session on Biochemistry of EXT’s, Marion Kusche-Gullberg of the University of Upsala, Sweden spoke about “EXT 1
and 2 proteins and heparan sulfate biosynthesis.”  Jacqueline Hecht’s presentation was entitled: “EXT1 and EXT2 Germline
Mutations are the Most Common Cause of Diminished Heparan Sulfate in Exostosis Growth Plates” (Jacqueline T. Hecht,
Elizabeth Hayes, Catherine R. Hall, Hong Li, Richard Haynes, William Cole, Robert Long, Mary C. Farach-Carson, and Daniel D.

During the Session on Bone Development and Repair, Henry Kronenberg, Massachusetts General Hospital and Harvard Medical
School spoke on “Actions of parathyroid hormone-related protein on the growth plate,” T. Michael Underhill, University of
Western Ontario spoke on “Importance of RAR-Mediated Gene Repression in Skeletal Development” (T. Michael Underhill, Lisa M.
Hoffman and Andrea D. Westen), and Yoshihiko Yamada, National Institute of Dental and Craniofacial Research, National
Institutes of Health, spoke on “Perlecan mutations in mice and humans: critical role of perlecan in skeletal development.   

Speaking on Other Bone Disorders were Benjamin Alman, the Hospital for Sick Children, Toronto, who discussed “Hedgehog
and Parathyroid hormone-related protein signaling in enchondromatosis,” and Frederick Kaplan, University of Pennsylvania
School of Medicine, whose presentation was entitled “MHS: Multiple Hereditary Skeletons – An Enchondral Conundrum”
(Frederick S. Kaplan, M.D., Lourdes Serrano de la Pena, Ph.D., Jaimo Ahn, Ph.D., Paul C. Billings, Ph.D. and Eileen M. Shore, Ph.
D.), and which described in great detail Fibrodysplasia ossificans progressiva (“FOP”).

EXT Function in Morphogenesis was covered by several speakers.   David Ornitz of the Washington University School of
Medicine spoke on “FGF Signaling in Skeletal Development” (Kai Yu, Zhonghao Liu, Ann Jacob, David Ornitz).  Dan Wells,
University of Houston spoke on “Non-exostoses related alterations in the EXT 1 deficient mice” and Jeffrey Esko, University of
California – San Diego spoke on “A Murine Model for Hereditary Multiple Exostoses (HME)”  (Beverly M. Zak, Dominique Stickens,
Dan Wells, Glen Evans, and Jeffrey D. Esko).   This team has produced a mouse model to understand how a change in heparan
sulfate biosynthesis might result in exostoses. The significance of mice having MHE cannot be understated, as mice can be bred
in large numbers allowing research to proceed faster, and as the findings in mice can be related to MHE in humans.  

The next group of speakers on this subject discussed research using Drosophila (fruitfly) models. In Drosophila with EXT 1 and
EXT 2 mutations, MHE is exhibited in their wings.   Signaling patterns found in EXT 1 and EXT 2 in the mice correlate with those
found in EXT 1 and EXT 2 Drosophila.  Rahul Warrior, University of California-Irvine, spoke about “Modulation of growth factor
signaling by the ext2 tumor suppressor gene” (D. Bornemann, W. Staats, J. Duncan, S.B. Selleck, and R. Warrior).

Gyeong-Hun Baeg, Howard Hughes Medical Institute, Harvard Medical School spoke on “The role of HSPGs in formation of the
Wingless gradient in Drosophila” (Gyeong-Hun Baeg, Erica Selva, Norbert Perrimon).  Siu Ing (Inge) The, University of
Massachusetts Medical School, spoke on “The role of Drosophila EXT1 homolog tout velu in Hedgehog distribution.” Scott
Selleck spoke about “Proteoglycans as regulators of grown factor/morhpogen distributions in tissues”
(Jaime Reuter, Ross Waldrip, Xiabo Chen, Will Staatz, and Scott Selleck).
First MHE Research Conference 2002
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