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COMER 4 ~EWI ~ ED F~ONS mis that lists the areas of research that, In me view of the cx~nittee am works p participants, hold particular precise In advancing the knowledge base and efficacy of medically assist conception for hogans and other animals. In ablution, this *I airlines ache conclusions arm specific ~ ations ~ at were made by the ~ nittee following the workshop. m e research agenda items are organic ~ into three ma m categories. m e first and largest category includes promising areas of basic scientific investigation. me second category encompasses areas in which~improvements in technology are needed. me third category includes questions that can be approached tar Operative agreements ~ng - In addition to organizing the rearm agenda ink Camden areas, these categories also genially reflect the different furring Humanisms that might be r~ui~ to support such investigations. Reseal grants to short basic science proteges c~ct be obtained through competitive grant programs at the National Institutes of Hearth or the National Science Fcun~ation. Formula funds and competitive grants can be obtained from the United State= Department of Agriculture. Technological development, however, cculd be supported by contracts from projects already supported by the NIH or other agonies. Coordination of information fern IVES clinics ~1d be accomplished by any one of a number of agencies or professional societies. cl Mom centers involved in IVFET. , ~ ~ ~ . heat Alert the topics list belter are areas ~ which further research was r~ect by workshop participants and cammit~cee is. It therefore reflects the areas of investigation considered to be promising by the cammitt~. Work ~ these areas Is ~t~ ~ ~ urxi~a~ of the biology of repr~uctior~ with the hoe that i~as~ knowledge will eventually lead to imp~v<3rents In practice of IVES In humans or other animals, or to advances In the area of oc~ntra~ion. PA areas are listed here in s ~ nary fort arm a ~ ly belch to 1 ~ r ani ~ s art human beings unless specifically noted. The reader should refer to Chaptar 2 and the papers published in Appendix A for detail ed di.~lm~ion of these areas. noetic Shims Male Gamete genesis o Definition of the role of Ceil adhesion mulches in interactions between Serboli cells and developing sperm cells. - 86 -

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o U~i~ the fashion of differential preen synthesis In different stages; of swam develc~Tt. O Determination of the role of paracrine factor include fib~last growth factor, sc~at£~in C, epi~lermal growth factor, arm Ricers 1 con ache develc~: arm differ~iatioa~ of due gamete:. O Seal analysis to identify r~or~1 and abnormal in and Me development of markers; for all sperm. O ~erstar~ of ache bi~istry of sperm capacitation. Female G~0genesis o Analysis of ~ effete of Ration or hormonal stimulation pro~Is on ooze development arx] Reaction. This work chard also examine riffles among sp~ies. O D~elc~~e~~~ of ways to mature octal; In vitro. O Investigation of ways to naturally stipulate oocyte arx] folliadar de~relc~nt. O Tr~restigation ~0 the biochemistry of Clitic art and the factors;, such as cyclic Al, purines, Acing, and maturation-pr~r~ting factor, that may mediate this pma~;s. O Devel~nt of ways to produce or synthesize hormone from non-h~nan primate to be ·~.~ ~ varian stimulation. O Definition of ~ e role of ovarian estrogen in ooc ~ e mab~ration and cvulation and the interactions between estrogen and paracrine factors including fibroblast and epidermal growth factors, insul Unalike Growth factor, transforming growth factor, and inhib~n. O Definition of the point at which oocybes become sensitive to factors that influence their development. : 0 Elucidation of the processes that underlie oocyte depletion, to determine why oocytes are 106t at a predictable rate throughout life. O Investigation into ways to augment natural hormone release. O Investigation into the biochemistry of protein synthesis and modification in ovarian cells. — 87 —

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Fertilization o Investigation into the bic~hysics of ~~l n~nbr~ as it relate to Sperm arm egg iT~racti~ at fertilization. O ~ntirn~ investigation to identify ~ genes for zone proteins ~ variant pecies, especially he. O Further delineation of the role of zone proteins, e~ially ZP2 am ZP3, ~ An birdie. o Notary of Me bi~istry of Me modification of zone proteins in pr~rentir~ polyp i. O ~1uciclation of Me Altar clet~ina~ of antibody formation ~ zone proteins arx] their poss ible role in contraceptive st:ra~ies;. O Definition of ache bi~ni~a~ Anise of the cortical reaction In the egg and He effects of this reaction on zone proteins. o Determination of the physiologist significance of germinal vesicle breakdown and the biochemistry of sperm chromat~n Recondensation. O Definition of the molecular events associated with formation of the male and female prunuclei. O Definition of the molecular events during zygote formation and the first cleavage. Preimplantation Development o Definition of the metabolic requirements of early embryos at different stages. o Determination of embryonic gene expression. O Assessing the potential of individual embryonic reals and defining the point at which embryonic meals are committed to particular fates. O Identification of substances procure by early embryos that signal~changes An the uterus prior to implantation. 0 ~nproverrents in embryo multiplication and embryo splitting, especially for food-producir~ animals. — 88 —

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Placation o Definition of ~ bi~ni~a~ events that make the uterus live to implantation. O Definition of He factors rely by ~6 Cat cay- erxiametrial Clarke at ache site of i~planation. O Identification of the role of embryo relays factors suppressing the Irene responses of the Bother. o Isolation and analysis of Stan rely by er~c~metrial fells ark their effects on embryos. O Continued work with In via newels of human implantation to stay the bioc~heaistry and Humanisms of embryo~ometrial interactions, e ~ city the role of extracellular matrix proteins ark the bio Misery of troph~blast invasion of the endometrium. - Technological Advances 0 Improved crimp ~ tion techniques, including freezing and thawing protocols for eggs and emb Eros. O Improved resolution of ultrasonography for localization and noninvasive harvest of oocytes, eggs, and embryos-~would have particular usefulness for non-human primates and food-pro*ucing animals. o Development of new culture media and methods for in vitro maturation of oocytes. o Development of safe methods of biopsy of early embryos for preimplantation diagnosis of genetic diseases. Clinical Research Opportunities m e following areas are thou in which a coordinated data collection effort across [VFET clinical centers would improve the quality and success rates of IVFET nationally and, possibly, internationally. O Evaluation of hormonal stimulation protocols in terms of namer of oodles handy, quality of of;, and rate of fertilization sums . O Station on the incidence of Normal implantation rat== in TV=T practice arm oorrelation of incidence with particular stimulation prat~l use. - 89

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o C~le~ion of information r~3i~ Me incite of abr~rmal eggs and embryos, failed fertilization, and develc~nta1 arrest of Mayor. O A}~aly~;= of data pertaining to ~ization of embryonic stage with er~netrial stage and ~relc~ of ~xx3s ~ improve r~ization. O Collection of information on Waring of Ire yes are an embryos for r~ i. ConclusiorY; are ~atic~ns Deveining Pleat Policy the la~ of a melanism for dealing with ethical disagreement cover the ~~ of embryos in r~ he slay the rate of priory; in r~r~ by, in effect, placing a moratoria on the I of f~ fuTxis for eight years;. This has had urxI-=irable r ~ ts: the human clinical practice of [VFET is less effective than it might have been had research progressed at a faster pace; other socially desirable goals such as improved contraception, better techniques to preserve endangered species, and more cost-effective methodic of producing food have develcged at a pace slower than is Optimal. m e recent appointment of the Bicmedica1 Advisory Commit ~ e by the Bicmedi~al Ethics Board, to report to Congress by November 1990 on embryo research issues, could be a step toward a solution. The committee also applaud= the intention to revive the Ethics Advisory Board of the Department of H~a1th and Human &rvi ~ to rule on the ethical acceptability of research redating to human embryos, which is required before federal funding of such a research grant can be reconsidered. However, until these grc ups became fully functional and show evidence of progress, the Or impact must remain in question. If these grcup6 can assume leadership roles in resolving the difficult issues of reproductive research, and develop guidelines for research that are based on information provided by science, as well as on conchs that are ethic accruable to society, rehears in r~pr~ion will be able ~ move forward. ~ _ .. . . ~ . Blat if th - ;e grope; }fine paralyzed bray of political ~;iderations or an inabiiit~r to dlevelcE? a frank for Ache resolution of cliffer~es of Minion, another organization shard take over the role. m e ~ Soiree r ~ ~ at, if the groups currently being formed fail to come to conclusions concerning embryo and fet=1 research, a eon-go vern=ental organization should be established to develop guidelines for embryo and fetal research based on the moat advanced knowledge that science can muster, and with serious Consideration of the expressed values of society. The group should be — 90 —

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composed of individuals ~ Oh expertise in the relevant scientific disciplines. representatives of the lay public, and experts ~ the legal, ethical and social issues. m e organization should be housed in an institution that would allow it to conduct its deliberations free from undue pressures from political am special interest grcup6. A model for such activities can be found in the Voluntary Licensing Authority of Great Britain. This group was established after a governmfrta1 committee reed a statutory licensing authority. Prizing that it well] be sane time before legislation Waco be completed, the Midas Heard Ail arm the Royal Collie of ~Etriciar~ jointly Awry the rolul2tary body. Five of its 13 DINS are lay people. The group has a mandate to remake five major activities: 0 to approve a ~ of practice can r~r~ relate to Hun fertilization arm embryology; o to invite all centers, clinicians and scientists engaged in research on IVF to submit their work for apprcNa1 and licensing; o to visit each center before it is granted a license; o to report to the sponsoring organizations; and o to make known publicly the details of both approved and unapproved work. Basic Science Foundations The number and range of topics included in this chapker's research agenda indicate the exciting potential for prc~uctive scientific exploration. Funding that would allow investigation of the areas targeted in the research agenda would allow significant advances to be made in understanding reproductive processes. me committee believes that fundamental research to enhance the hectic science foundations of reproductive biology should be stimulated and supported. This includes studies of human beings, laboratory animal models, and food-producing animals. The knowledge that scald be generated is fundamental to an understanding of how to reverse infertility, to new approaches in the area of contraception, and to increasing the world's food supply. This report attempts to define not only the state of knowledge in reproductive science relating to IVFET, but to a~=-== and highlight some research opportunities. It is important that aspects of mane as well as female reproductive biology be studied. It ~s-also important that investigators make Bale of some opportunities that are largely ignored inlay. These cpportunities occur as a result of clinical activities as - 91 -

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well as r~i activities. For example, eggs that have failed to become fertilized can becx~re material for studies seeking c~1 abnormalities. Fertilize Ad; that fail to develc~ may be used to investigate the reasons for develQta1 failure, and to answer questions abaft the natural Stage that ours; in pregnancy. l ~ e ~ of this ~ pe ~ Id ge ~ lly be funded by the grant mechanisms of the National Institutes of Health and by the United Stat Department of Agriculture. For adequate attention to a research agenda, however, administrators of NIH need reshanJsrs to insure that studies on a variety of these tonics are being funded. For this an REP or a contract mechanism might be Century to insure adequate coverage of the various ads of reproductive biology. Formations are also encage to consider Ivan support for basic shies in reproduction. A stable fending base for reproductive r~ will Urge yours, well-train~ scientists to pursue red in r~pr~tive biology. me Remittee Hers that a vigorous program for fur~irn of a basic science agenda ~ pr reductive biology be maintained In a ~ rdinated fashion by an appropriate office in the National Institutes of Health. Applied Breath Research neons to be stimulat ~ concerning technologies used in medically assisted conception ~ food producing animals and in human beings. Lack of sup port in these areas is leading to inadequate scientific underpinnings for safe and effective clinical practice. An example of a technique used, but not carefully evaluated for possible detrimental effects, is freezing eggs or zygotes. Further experiments should be conducted to chic the effects on safety and viability of this ~no~oq~r With is starKiard Practice ~ B~ {v~ clinic;. Other areas ~ ~ — — — ~ ~ ~ of technology that need to De ~evelc pea Include Bees Invasive ways JO retrieve oocytes, ways to mature oocytes ~ vitro, and ways to a~==== the quality of spermatozoa or oodles to be up for fertilization. Since these st~ies Old be trilogy driver, it is unlikely that the Search will be furred by a grant Panic, therefore a contract Dig Child be used. lhe committee r~s that applied reseal into technologies used in medically assisted oonoeption be undertak ~ to provide a firm foundation for the safe and effective practice of in vitro fertilization and embryo transfer. Such applied research should be coordinated by the appropriate office at the National Institute_ of Health. 92 —

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Clinic Rearm O~or~nities i; Me ~ bevies miss Opportunity ~ the failure ~ learn freon me diverse experience:; of the acutely 160 clinical program that pra~ride hymn Inter. In mention to scientific Scions, there are Lions ~ do with ~ organization of clinics; and the ~ of pr~ur~. He answers to these Dims ~1d enable practitioners work more effectively, arm enable policy makers trike decisions on the basis of the best available information,. Sum questions include: To pearl - ; the quality a~ura~ for facilities and pi use Sinclair the training of thcx;e providing servioes)? }per are protocols veloped? Hear starboard are they? ~ at are the cuticles for each protocol? What is the role of Institutional Review boards in the establishment and maintenance of clinical facilities? Some specific que ~ ions to be answered frill data that could be collected frog clinics include: What ovarian stimulation protocols are the most successful? Is chrocoscmal damage associated with any of the procedures \~=P~? What indicates whether a zygote will implant su~=fully? Much data relating to scheme questions already exist In the cementers. Other questions may retire a cooperative prospective stay to be Overtaken. Clinics IFFY centers can also provide unique Amities for important s ~ ies. For example, human eggs ~ at fail to fertilize In vitro are material that could be used to investigate the p enomenon of failed fertilization. Improved understanling of reasons for failure has implications for reversing infertile ity and ensuring conception. Another area for investigation for which the rVFET centers are particularly suited is arrested zygotic development. In producing embryos by in vitro fertilization, it has been noted that certa ~ zygotes step dividing. The reasons for such arrested zygotic development are unknown. Have these cells died? Can one tell four studying the newly dividing zygotes which ones will be most likely to initiate a successful pregnancy? Failed fertilization in the pert-implantation period in both the natural situation and during the procedures of FRET is an important area to be understood. Develc~tal failure ~ the early stages of embryonic vel~nt appears to be a normal event for ache human species. Nether this loss results fmn lethal genetic defects, choral anomalies, bio~emit~a~ or structure abnor~itics, or technical cliffia0ties news further elucic3ationO ~ rch that s ~ to ur~erstar~ the ban = of reprc~uctive failure, and its relationship to hyperstimulation should be enocuraged. Coordinated studies utilizing the mass of material and experience from [VFET centers could begin to answer these and other questions. In addition, the experience of centers performing IVFET for farm animals could provide val amble information. - 93

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The Unit atlas: the activities of ache various professional societies that have issued n~-bir~i~ subagents am He quality of practice of IVF. Ibe African Fertility Society has also prcnrid"1 a votary registry for cam;. On ache animal side, He American Embryo Transfer Society has start to establish sane Parity Ares for cxx~remialbavineen~ryo transfer. States ~ngereral get involved by limping physicians, hospitals, art clinics, art as yet have net played a dominant role In assuring quality of Am. ~ canmi~ee believes that a Manic Is no to Orator and evaluate clinical practice so ~ at existing information ~ at Is relatively easy and inexpensive to collect can be disseminated. This would enable clinicians to build on the broadly based experience of the community and help ensure that patients have arc=== to information about develcpments in [VFET and to well-informed physicians. me committee recommends that a mechanism for multi-centered data collection be established to monitor and evaluate human and veterinary practice= of medically ~==isbed conception in order to improve the safety, effectiveness and quality of clinical practice. A cooperative group conpcEed of the relevant professional societies should be established to fund and initiate data oollection under the direction of an ~ntar-society council conFored of representatives of each participating organization. Improving Communications The ICM Workshop on Medically Assisted Option brought together Seaters frown basic science, clinical practioe, art anility sciences. the resulting interaction was view as extremely helpful by investigators fern each of these ca~nunities. The committee is that a Onanism (or multiple mechanisms) be fat for fostering oonti~med cc~im~tion between resealers In diverse areas of reproductive science. the initiative should cc me bob fern NIH research administrators who cad sponsor additional workshop c~or~itiec and fan the prof~=iorn1 societies either individually or through an ~ntersociety council. - 94 -