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• W2023304848 abstract "SURGICAL TRAINING and research never ends for the modern pediatric surgeon. Research for surgery is a lifelong process; a difficult problem may take more than 20 years to unravel. However, investment in research is worthwhile because a single finding impacting a disease may affect many patients or possibly a whole society. For example, when effective treatment for tuberculosis was introduced, sanitoria around the world closed, and the direction of thoracic surgery changed forever. The plague scourged the world, killing untold millions over the centuries, each event usually ending with a scorching fire that killed both rats and fleas but also destroying whole cities in its wake. Plagues were so common that nursery rhymes sung the clinical symptoms. Ring around the roses,A pocket full of posiesAchoo, achooWe all fall down “Ring around the roses” described the characteristic skin lesions, a rubaceous pustule surrounded by a ring. People carried amulets of posies in their pockets to ward off disease. Forceful sneezing, which spread the disease, was soon followed by collapse, coma, and death. Imagine such grim events reflected in the rhymes of children! A cure for the plague virtually ended this cyclic scourge. The cure of septic shock changed the face of our obstetrical wards forever. I can recall from the last years of medical school at Columbia College of Physicians and Surgeons, 14- and 15-year-old frightened young girls in the final stages of mortal septic shock before we employed massive doses of antibiotics, steroids, and fluid replacement coupled with central venous monitoring. Consider the staggering cost that diabetes imposes on our modern health systems. A salutary discovery may dramatically affect the entire landscape of medical and surgical practice of the future, and may even divert the seemingly inexorable advance of obesity. It is the knowledge that one small change may turn “on a dime,” the nature of clinical care. One discovery may make a difference; that is the compelling draw, the forceful grip, and the fervent dream of research. I firmly believe that we must strive to understand the molecular mechanisms of disease to devise sensible management of disease and that a study of outcomes of disease must be used in this context to constantly adjust management as new knowledge becomes available. To illustrate the lifelong research investment required, I discuss an old hypothesis first proposed at the American Pediatric Surgical Association many years ago. The experimental results emanating from this hypothesis have produced a product poised for clinical application. I also discuss a new hypothesis about an old and nagging clinical problem that may suggest new therapeutic strategies and direct future research. Over the years, our research in the Pediatric Surgical Research Laboratories of the Massachusetts General Hospital has been driven by phenotypes of human disease. In caring for and reconstructing children with intersex disorders, we became aware of molecules prominent in normal sexual differentiation, the well-known testosterone, which stimulated growth of tissues destined to become male, and müllerian inhibiting substance (MIS), which caused normal growth arrest and apoptosis in tissues destined to be female. Our investigations of MIS slowly deepened our understanding of normal sex differentiation and of the congenital abnormalities that developed as a result of genetic mutations that caused the defects. We knew about testosterone, estrogen, and the gonadotropins early in the course of these studies, then became aware of MIS.1Teixeira J. Maheswaran S. Donahoe P.K. Mullerian inhibiting substance An instructive developmental hormone with diagnostic and possible therapeutic applications.Endocr Rev. 2001; 22: 657-674Crossref PubMed Scopus (277) Google Scholar In the early 1990s, knowing that the Y chromosome somehow directed male sexual differentiation, the scientific world was heartened by the discovery that the genetic switch of male sex differentiation was initiated by SRY (the Sex determining Region of the Y chromosome).2Koopman P. Munsterberg A. Capel B. et al.Expression of a candidate sex-determining gene during mouse testis differentiation.Nature. 1990; 348: 450-452Crossref PubMed Scopus (680) Google Scholar The small SRY protein directed gonadal differentiation in the mammalian urogenital ridge along the male lineage, and the resulting testes produced MIS, which caused regression of the müllerian duct, the anlagen of the uterus, fallopian tubes, and the upper vagina. Subsequently, testosterone was produced by the differentiated testes, causing stimulation of the Wolffian duct structures. Over the next decade, our knowledge of gonadal differentiation and our understanding of gonadal agenesis syndromes deepened but remains incomplete. For example, we know that at the time of primitive streak formation and gastrulation, the intermediate mesoderm is induced to form the indifferent urogenital ridge under the influence of a number of transcription factors, and we now associate a number of disorders with abnormalities of these factors.3MacLaughlin D.T. Donahoe P.K. Sex determination and differentiation.N Engl J Med. 2004; 350: 367-378Crossref PubMed Scopus (253) Google Scholar Mutation of the Wilms’ tumor gene (WT-1)4Hammes A. Guo J.K. Lutsch G. et al.Two splice variants of the Wilms’ tumor 1 gene have distinct functions during sex determination and nephron formation.Cell. 2001; 106: 319-329Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar is associated with both gonadal agenesis and renal agenesis in Frazier’s syndrome or the Denys Drash syndrome; steroidogenetic factor (SF-1) mutations result in both gonadal agenesis and adrenal agenesis.5Lala D.S. Rice D.A. Parker K.L. Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I.Mol Endocrinol. 1992; 6: 1249-1258Crossref PubMed Scopus (505) Google Scholar Later differentiation to testes is determined by SRY2Koopman P. Munsterberg A. Capel B. et al.Expression of a candidate sex-determining gene during mouse testis differentiation.Nature. 1990; 348: 450-452Crossref PubMed Scopus (680) Google Scholar and SOX9,6Wagner T. Wirth J. Meyer J. et al.Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.Cell. 1994; 79: 1111-1120Abstract Full Text PDF PubMed Scopus (1261) Google Scholar mutations of which result in pure gonadal dysgenesis. It is conceivable that overexpression of DAX-1 (Duplicated in Adrenal Hypoplasia Congenita on the X Chromosome) can lead to mixed gonadal dysgenesis. Thus, we can now analyze gonadal agenesis in the context of mutations in genes such as WT-1, SF-1, SOX9, DAX-1,7Zazopoulos E. Lalli E. Stocco D.M. et al.DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis.Nature. 1997; 390: 311-315Crossref PubMed Scopus (359) Google Scholar and SRY. Intersex abnormalities also have a genetic basis in mutations causing too much testosterone, as in the case of female psueohermophroditism or congenital adrenal hyperplasia,8New M.I. Prenatal treatment of congenital adrenal hyperplasia. The United States experience.Endocrinol Metab Clin North Am. 2001; 30: 1-13Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar or too little testosterone as well as failure of response to testosterone,9Brown T.R. Lubahn D.B. Wilson E.M. et al.Deletion of the steroid-binding domain of the human androgen receptor gene in one family with complete androgen insensitivity syndrome Evidence for further genetic heterogeneity in this syndrome.Proc Natl Acad Sci U S A. 1988; 85: 8151-8155Crossref PubMed Scopus (173) Google Scholar and mutations of MIS or its receptor, which cause forms of male psueodohermophroditism.10Belville C. Josso N. Picard J.Y. Persistence of Mullerian derivatives in males.Am J Med Genet. 1999; 89: 218-223Crossref PubMed Scopus (105) Google Scholar Our work with MIS was inspired by the elegant and seminal experiments of Alfred Jost, who, in the late 1940s studied sexual differentiation in the rabbit embryo.11Jost A. Recherches sue la differentiation sexulle de l’embryonde lapen.Arch Anat Microsc Morphol Exp. 1947; : 379-418Google Scholar Research dollars were not available; hence, he hunted rabbits in the Bois de Boulogne and used the indigenous Géant Des Flandres rabbits, which, to his good fortune, weighted 7 kg and were refractory to abortion when their uterus was surgically invaded. He gonadectomized females and replaced the gonads with either testes, testosterone pellets, or nothing. Under the influence of the testes, the Wolffian ducts were stimulated, and the müllerian ducts regressed. In the presence of testosterone pellets, the Wolffian ducts were again stimulated, but the müllerian ducts persisted. With no treatment, both müllerian ducts persisted and Wolffian ducts regressed. He thus concluded that testosterone was necessary to stimulate the Wolffian ducts and that another nonsteroidal substance, which he named the müllerian inhibitor caused regression of the müllerian duct. A number of laboratories later attempted unsuccessfully to repeat these experiments; however, they used rabbits specially bred for the laboratory, the New Zealand white, which weighed only 2 kg and aborted with minimal stimulation of the pregnant uterus. In 1969, Picon12Picon R. Action of the fetal testis on the development in vitro of the Mullerian ducts in the rat.Arch Anat Microsc Morphol Exp. 1969; 58: 1-19PubMed Google Scholar removed the urogenital ridge from embryo rats for study in organ culture. Josso’s laboratory in the Enfant Malades in Paris modified this assay and, using it, found that the Sertoli cells of the seminiferous tubules were responsible for the müllerian duct regression and began to use this assay to purify MIS from fetal testes.13Josso N. In vitro synthesis of mullerian-inhibiting hormone by seminiferous tubules isolated from the calf fetal testis.Endocrinology. 1973; 93: 829-834Crossref PubMed Scopus (76) Google Scholar Somewhat later, our laboratory in Boston independently modified the organ culture assay14Donahoe P.K. Ito Y. Marfatia S. et al.The production of Mullerian inhibiting substance by the fetal, neonatal and adult rat.Biol Reprod. 1976; 15: 329-334Crossref PubMed Scopus (43) Google Scholar and began to purify MIS from newborn calf testes,15Donahoe P.K. Ito Y. Price J.M. et al.Mullerian inhibiting substance activity in bovine fetal, newborn and prepubertal testes.Biol Reprod. 1977; 16: 238-243Crossref PubMed Scopus (61) Google Scholar because we were intrigued by müllerian duct apoptosis, which was characterized by autophagocytosis of adjacent epithelial cells, condensation of mesenchyme around the basement membrane of the epithelial müllerian duct, breakdown of the basement membrane, and both death and epithelial/mesenchymal transformation.16Trelstad R.L. Hayashi A. Hayashi K. et al.The epithelial-mesenchymal interface of the male rat Mullerian duct Loss of basement membrane integrity and ductal regression.Dev Biol. 1982; 92: 27-40Crossref PubMed Scopus (140) Google Scholar This bioassay was subsequently used over the years to purify bovine MIS and to clone both the human and bovine MIS gene.17Cate R.L. Mattaliano R.J. Hession C. et al.Isolation of the bovine and human genes for Mullerian inhibiting substance and expression of the human gene in animal cells.Cell. 1986; 45: 685-698Abstract Full Text PDF PubMed Scopus (781) Google Scholar We found homology of MIS to the tumor growth factor beta (TGF-β) and Inhibin genes that were cloned 5 months earlier and to Dicapentaplegia, which was cloned 6 months later, leading to the formation of a family of genes known as the TGF-β family, of which, MIS is a distant member. We then produced larger amounts of recombinant human MIS and evolved methods of purification.18Ragin R.C. Donahoe P.K. Kenneally M.K. et al.Human Mullerian inhibiting substance Enhanced purification imparts biochemical stability and restores antiproliferative effects.Protein Expr Purif. 1992; 3: 236-245Crossref PubMed Scopus (61) Google Scholar, 19Lorenzo H.K. Teixeira J. Pahlavan N. et al.New approaches for high-yield purification of Mullerian inhibiting substance improve its bioactivity.J Chromatogr B Analyt Technol Biomed Life Sci. 2002; 766: 89-98Crossref PubMed Scopus (35) Google Scholar Because MIS induced apoptosis of the müllerian ducts, we hypothesized that it may cause apoptosis against endometrial, cervical, and fallopian tumors of müllerian duct origin as well as ovarian cancers that emanate from the müllerian coelomic epithelium surrounding the ovary.20Donahoe P.K. Swann D.A. Hayashi A. et al.Mullerian duct regression in the embryo correlated with cytotoxic activity against human ovarian cancer.Science. 1979; 205: 913-915Crossref PubMed Scopus (58) Google Scholar We cloned its type I21He W.W. Gustafson M.L. Hirobe S. et al.Developmental expression of four novel serine/threonine kinase receptors homologous to the activin/transforming growth factor-beta type II receptor family.Dev Dyn. 1993; 196: 133-142Crossref PubMed Scopus (143) Google Scholar and type II22Teixeira J. He W.W. Shah P.C. et al.Developmental expression of a candidate mullerian inhibiting substance type II receptor.Endocrinology. 1996; 137: 160-165Crossref PubMed Scopus (95) Google Scholar receptors, which were found to be homologous to other members of the TGF-β family of receptors; studied its downstream signal transduction pathway; investigated its ability to suppress steriodogenesis in Leydig cells; defined the clinical use of MIS in ovarian, breast, and prostate cancer; explored novel delivery systems for MIS; then produced MIS in tobacco and subsequently in milk.1Teixeira J. Maheswaran S. Donahoe P.K. Mullerian inhibiting substance An instructive developmental hormone with diagnostic and possible therapeutic applications.Endocr Rev. 2001; 22: 657-674Crossref PubMed Scopus (277) Google Scholar The MIS gene led to the production of a 140,000-molecular-weight homodimer protein, which was activated by cleavage and secreted into the media from which it was then purified to relative homogeneity. Antibodies were raised to purified human recombinant MIS and used to design a specific and sensitive immunoassay using both monoclonal and polyclonal antibodies.23Hudson P.L. Dougas I. Donahoe P.K. et al.An immunoassay to detect human mullerian inhibiting substance in males and females during normal development.J Clin Endocrinol Metab. 1990; 70: 16-22Crossref PubMed Scopus (224) Google Scholar This detection system used at both the MGH and the Enfant Malades and subsequently by Mary Fallat in Louisville and John Hutson in Melbourne, has been extremely helpful in analyzing patients with intersex abnormalities because the presence of MIS in the newborn can only occur in a testes. Granulosa cell tumors can produce high levels of MIS; the MIS Elisa can be used to detect the presence or the recurrence of the tumors long before they can be detected by computed tomography (CT) scans. David McLaughlin, the Associate Director of the laboratory, who designed the purification schemes and the MIS Elisa, has been personally responsible for the scientific training of many accomplished pediatric surgeons and scientists over the years. The MIS type II receptor was cloned in this laboratory by Jose Teixeira and by a number of other laboratories, and probes were used to detect the presence of receptor mRNA in the mesenchyme surrounding the müllerian duct and in the gonads. Antibodies developed to the receptor recognize the protein in testes, ovary, ovarian cancer, normal ovarian coelomic epithelial cell lines, uterus, cervix, and pituitary, with transient localization in the embryonic lung. These expression patterns are extremely important in instructing us in how MIS can be used as a therapeutic. Persistent müllerian duct syndrome is a rare form of male psueohermophroditism resulting from either mutations in the MIS ligand or in the MIS type II receptor. The same phenotype of retained müllerian ducts can also occur when an MIS type I receptor was inactivated,24Jamin S.P. Arango N.A. Mishina Y. et al.Requirement of Bmprla for Mullerian duct regression during male sexual development.Nat Genet. 2002; 32: 408-410Crossref PubMed Scopus (304) Google Scholar providing proof that the type I receptor is required in the genetic pathway of MIS action in the urogenital ridge. After cloning a number of type I receptors for MIS and other members of the TGF-β family in the laboratory, we began to work out the downstream signaling pathway for MIS, which usurps BMP-specific Smads 1, 5, and 8 to activate further downstream signals.25Visser J.A. Olaso R. Verhoef-Post M. et al.The serine/threonine transmembrane receptor ALK2 mediates Mullerian inhibiting substance signaling.Mol Endocrinol. 2001; 15: 936-945Crossref PubMed Scopus (141) Google Scholar, 26Clarke T.R. Hoshiya Y. Yi S.E. et al.Mullerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)-like pathway mediated by ALK2 and induces SMAD6 expression.Mol Endocrinol. 2001; 15: 946-959Crossref PubMed Scopus (155) Google Scholar Parallel downstream signal transduction pathways for MIS have been elucidated in ovarian cancers, which we hypothesized would be a therapeutic target for MIS based on fact that 95% of human ovarian cancers emanate from the coelomic epithelium, which coats the ovary, the same coelomic epithelium that invaginates in the embryo to form müllerian derivatives, fallopian tube, uterus, cervix, and upper vagina. This coelomic epithelium is subjected to multiple follicular ruptures during the lifetime of the normal human female, to whom this type of ovarian cancer is unique.27Fuller Jr, A.F. Krane I.M. Budzik G.P. et al.Mullerian inhibiting substance reduction of colony growth of human gynecologic cancers in a stem cell assay.Gynecol Oncol. 1985; 22: 135-148Abstract Full Text PDF PubMed Scopus (43) Google Scholar Cyclic growth stimulation by gonadotropins and follicular rupture of the surface epithelial at each ovulation may also contribute to the susceptibility of this tissue to tumor transformation. We found that a number of human ovarian cancer cell lines were responsive to MIS in in vitro assays and that they expressed MIS type II receptor by Northern analysis. Furthermore, ascites tumor cells removed from patients with stage III and IV human ovarian cancer bound labeled MIS, expressed the MIS type II receptor by reverse transcriptase polymerase chain reaction (RT-PCR) and were growth inhibited by MIS in stem cell assays.28Masiakos P.T. MacLaughlin D.T. Maheswaran S. et al.Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) type II receptor, bind, and are responsive to MIS.Clin Cancer Res. 1999; 5: 3488-3499PubMed Google Scholar Transfection of the activated MIS gene into OVCAR-8, a human ovarian cancer cell line that best expresses the MIS type II receptor, resulted in dramatic growth inhibition that was accompanied by induction of the p16 protein, a CDK inhibitor associated with G1 arrest in the cell cycle. Overexpression of p16 also caused marked grown inhibition of these same cells, which could be reversed by antisense p16.29Ha T.U. Segev D.L. Barbie D. et al.Mullerian inhibiting substance inhibits ovarian cell growth through an Rb-independent mechanism.J Biol Chem. 2000; 275: 37101-37109Crossref PubMed Scopus (83) Google Scholar Furthermore, MIS had a downstream affect on p130, a pocket protein homologous to retinoblastoma protein. MIS also upregulated the downstream responsive genes E2F1, 2, and 3, which are known to be responsible for eliciting an apoptosis cascade. Given these dramatic effects in vitro, a critical question remained; “does MIS work in vivo?” To address this question, we used the same cell lines that were responsive in vitro, fixed them in fibrin/thrombin clots, implanted them beneath the renal capsule of immunosuppressed mice, and found that whether we parenterally delivered the purified human recombinant MIS protein or delivered MIS from transfected cells enmeshed in an implanted biodegradable mesh to create an MIS producing neoorgan, both IGOV-1 human ovarian cancer in SCID mice and OVCAR-8 in nude mice were growth inhibited by MIS.30Stephen A.E. Masiakos P.T. Segev D.L. et al.Tissue-engineered cells producing complex recombinant proteins inhibit ovarian cancer in vivo.Proc Natl Acad Sci U S A. 2001; 98: 3214-3219Crossref PubMed Scopus (28) Google Scholar, 31Stephen A.E. Pearsall L.A. Christian B.P. et al.Highly purified mullerian inhibiting substance inhibits human ovarian cancer in vivo.Clin Cancer Res. 2002; 8: 2640-2646PubMed Google Scholar Thus, the supposition that MIS would work in vivo is feasible. We currently are exploring whether MIS can inhibit an oncogene-induced ovarian cancer tumor, which recapitulates human ovarian cancer in mice. These tumors were produced by expressing the SV40 T antigen oncogene driven by the MIS type II promoter, which directs expression of the T antigen transgene to tissues that endogenously express the MIS receptor. Cancers develop in the ovaries of the animals that look very much like human ovarian cancers and in time show widespread intraperitoneal metastases.32Connolly D.C. Bao R. Nikitin A.Y. et al.Female mice chimeric for expression of the simian virus 40 TAg under control of the MISIIR promoter develop epithelial ovarian cancer.Cancer Res. 2003; 63: 1389-1397PubMed Google Scholar Because we have noted in breast and prostate cancers that MIS modulates the immune system, we are very anxious to test MIS in these tumor models in immunocompetent mice. These studies are currently underway and may propel pharmaceutical development of MIS as a chemotherapeutic agent. Formidable challenges remain to create a homogeneous preparation of rhMIS with high biological potency and no toxicity, which can be produced at reasonable cost and stored for long periods.19Lorenzo H.K. Teixeira J. Pahlavan N. et al.New approaches for high-yield purification of Mullerian inhibiting substance improve its bioactivity.J Chromatogr B Analyt Technol Biomed Life Sci. 2002; 766: 89-98Crossref PubMed Scopus (35) Google Scholar Making sufficient amounts of MIS in mammalian cells for clinical trials may not be cost effective. Other more feasible modes of producing MIS include expression in tobacco or in goat milk; encapsulation of MIS in slow release capsules, either alone, or linked to another cytotoxin; the development of MIS type II antibodies and vaccines; and the development of peptide mimetics that can either act downstream of the receptor or can activate the receptor. A phase I clinical trial has been designed to use any one of these alternative approaches. Thus, a journey from dream to reality may be reaching fruition; it is easy to see that this journey has been a long one, characterized by early insights and successive advances and setbacks. However, when viewed over the perspective of time, progress has been steady, and the dream may become a reality. It is conceivable that all or most congenital abnormalities that we care for as pediatric surgeons are caused by gene mutations in a pathway important for the development and differentiation of the organ affected. As conserved pathways important for specific organ and system development are revealed, then the genes in those pathways will become obvious candidates as causes of congenital defects if mutated. We focused this “candidate gene” approach on congenital diaphragmatic hernia (CDH) because of its high mortality and morbidity and the fact that it could be diagnosed in utero and were confident that new technologies and sophisticated genetics could lead to a better understanding of the molecular defects that cause CDH. Furthermore, therapeutics and delivery systems could be designed from knowledge gained. Progressive fine tuning of various ventilatory therapies has led to better survival of this formerly highly lethal defect, but high morbidity persists. Although affected patients with congenital diaphragmatic hernia and their families are being collected and phenotyped, we focused on a candidate gene approach because many genes important in branching morphogenesis of the lung are conserved across species. Thus, we are using avian, Drosophila, rodent, and human models of lung development to uncover candidate genes and chemical modulators that could affect lung growth in patients with lung hypoplasia associated with congenital diaphragmatic hernia. While testing the ability of these genes to cause defects if mutated in the animal models, we are also looking for altered expression of these genes in lungs of human embryos with CDH compared with age-matched normal controls. We hope to prove the functional importance of these genes by rescuing abnormal lung morphenogenesis in the mutated animal models. Candidate genes then will be studied by mutational analysis of the coding region of the genes of carefully phenotyped patients. The entire Drosophila genome has been screened for genes that rescue larvae hypomorphic with a single gene mutation important for lung growth, and a small molecule screen has been designed using outgrowth of the first and second tracheal branches in larvae to discover new therapeutics. Similarly, a chick model is being used to uncover novel genes that are involved in lung development. A rodent model33Suen H.C. Bloch K.D. Donahoe P.K. Antenatal glucocorticoid corrects pulmonary immaturity in experimentally induced congenital diaphragmatic hernia in rats.Pediatr Res. 1994; 35: 523-529Crossref PubMed Scopus (94) Google Scholar has been designed to screen for new gene products and to confirm the functional importance of candidate gene products elucidated by the Drosophila and chick screens. Using candidate genes generated from these models, we can use whole genome mutational analyses and techniques such as loss of heterozygosity34van Slegtenhorst M. de Hoogt R. Hermans C. et al.Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.Science. 1997; 277: 805-808Crossref PubMed Scopus (1369) Google Scholar to look for differences in patients with CDH compared with normal family members. We will also study rare families in which multiple members are affected with CDH. The technique of comparative genomic hybridization35Lee C. Lemyre E. Miron P.M. et al.Multicolor fluorescence in situ hybridization in clinical cytogenetic diagnostics.Curr Opin Pediatr. 2001; 13: 550-555Crossref PubMed Scopus (15) Google Scholar is being used to screen the entire genome of patients with CDH and their families. Regions of deletions and transformations can be closely scrutinized to delineate smaller regions to uncover genes of interest. The MGH and Children’s Hospital in Boston are collaborating to analyze our joint patient populations, taking advantage of the unique and valuable multidisciplinary clinic organized at Children’s Hospital by Dr Jay Wilson and his colleagues.36Muratore C.S. Kharasch V. Lund D.P. et al.Pulmonary morbidity in 100 survivors of congenital diaphragmatic hernia monitored in a multidisciplinary clinic.J Pediatr Surg. 2001; 36: 133-140Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar In the overall plan, mutations in candidate genes will help to delineate common pathways affected by these candidate genes, and hopefully therapeutics can be designed rationally using genes or proteins known to create perturbations in that pathway. Translocations in the Philadelphia chromosome causing activation of the ABL gene were found in patients with chronic myeloid leukemia, which led to the rational drug design of tyrosine kinase inhibitors.37Rowley J.D. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining.Nature. 1973; 243: 290-293Crossref PubMed Scopus (3310) Google Scholar, 38Daley G.Q. Van Etten R.A. Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome.Science. 1990; 247: 824-830Crossref PubMed Scopus (1908) Google Scholar We hope to be able to make similar discoveries and uncover new therapies that can bring about better outcomes in our patients when combined with the already successful modalities of nitric oxide, extracorporeal membrane oxygenation (ECMO), surfactant therapy, and, most important, milder, gentler ventilation.39Fauza D.O. Hirschl R.B. Wilson J.M. Continuous intrapulmonary distension with perfluorocarbon accelerates lung growth in infants with congenital diaphragmatic hernia Initial experience.J Pediatr Surg. 2001; 36: 1237-1240Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar This study is in its infancy, yet the tools of genomics, proteomics, and rapid drug discovery may uncover new therapies for this frustrating anomaly. Furthermore, each one of our congenital anomalies could be analyzed by combining careful phenotyping of our patients with sophisticated genotyping of coding regions, 5′ promoter and enhancing regions, 3′ downstream regions of candidate genes, and subsequently intronic mutations. It is clear that there will not be a single gene defect for each congenital anomaly. Rather, we expect to reveal critical pathways affected from which to design therapeutics to modulate and ameliorate severe phenotypes. There are enough investigators in the American Pediatric Surgical Association to attack systematically all of the known congenital anomalies with which we deal. We must remember, despite financial and regulatory pressures, what it is that we love about surgery and why we chose our profession. Although the financial challenges are greater than any of us would have ever imagined, paradoxically, the influx of information technology, genomics, proteomics, and molecular and developmental biology have created the most exciting biological revolution ever known. Given these opportunities and challenges, our modern departments of pediatric surgery must inspire in our young faculty a passion to discover, change, and advance but in an area of individual choice so that the passion may be sustained. The state of the art is not enough; we must push the envelope in basic, clinical, and outcomes research, realizing that it may take a lifetime to solve a difficult problem.40Donahoe P.K. A lifetime of training for surgery. Boston Surgical Society Presidential Address, 2002Google Scholar Instead of departments with highly qualified competitive individuals, we must design our departments around cooperative interactive teams of discovery. Then we will collectively make a difference for our patients and for our society as a payback, our responsibility for all that we have been given. I owe thanks to 3 mentors who have provided inspiration and made this journey and this dream possible, M. Judah Folkman, W. Hardy Hendren, and W. Gerald Austen. Many others in our noble field of pediatric surgery have been inspiring. I thank the wonderful colleagues and fellows with whom I have worked over the years and with whom I have enjoyed the daily surge of discovery. Research and surgery have given a life of satisfaction and adventure. We have been blessed with a healthy loving family, a lifetime of challenging patients who have taught us great lessons, a host of technical advances, the compelling excitement of research, the marriage of research to clinical practice, and the satisfaction of designing clinical applications of one’s finding. In the course of your long journey into the future, I urge you to take the “road less traveled,” to avoid the race to publish, and to savor time to think. In the process, you will lose the fear of assailing the unknown. Things that once were obtuse will become clear as you accumulate a body of knowledge. Someday we may have the privilege of making a discovery. If not, we must be satisfied with the faith that this thoughtful, systematic approach will have the overall effect of improving the care of our patients in some other obscure context." @default.
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• W2023304848 title "Sustained inquiry: In the clinic and at the bench" @default.
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