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Northeastern University
BIOL 2301

Fetal research. John T. Hansen and John R. Sladek Jr. Science v246.n4931 (Nov 10, 1989): pp775(5). About this publication | How to Cite | Source Citation | NU Library Links Subjects Abstract: Research advances in the past 20 years have enabled the diagnosis and treatment of medical problems in the fetus before birth. Fetal research has revealed ways to detect congenital malformations and genetic diseases. Procedures such as ultrasound, amniocentesis (removal and analysis of amniotic fluid) and fetal heart rate monitoring are now widely used. It is also possible to give the unborn child blood transfusions and medication, and to even perform surgery to correct malformations in utero (in the uterus). Because of these research advances, the fetus has gained the status of patient. A related, but different, type of research involving the fetus is fetal tissue research, in which tissues from the dead fetus are studied; tissues are obtained from spontaneous and induced abortions. Fetal cells are valuable to medical researchers because they have unique physiological characteristics. For example, they grow and divide rapidly and can continue to grow after transplantation into another living organism. Fetal tissues may be used to treat and cure diseases in other fetuses, children and adults. One fetus with deficient immune function has received cells from two dead fetuses which may help it develop a healthy immune system. Transplants of fetal pancreatic cells may someday allow diabetics to produce their own insulin; fetal nerve cells may cure degenerative illnesses such as Alzheimer's disease and Parkinsonism. Fetal cell research may also help to develop vaccines, assess drug toxicity and treat AIDS (acquired immunodeficiency syndrome). These exciting possibilities must be balanced against the need to use fetal tissue in a responsible way and consideration of the complex moral and ethical issues involved. (Consumer Summary produced by Reliance Medical Information, Inc.) Full Text :COPYRIGHT 1989 American Association for the Advancement of Science. Due to publisher request, Science cannot be reproduced until 360 days after the original publication date. Fetal Research HUMAN DEVELOPMENT OCCURS IN TWO ENTIRELY DIFFERENT environments, one prenatal and the other postnatal. Prenatal development encompasses the embryonic and fetal periods, whereas postnatal development involves the passage through infancy, childhood, and adolescence to adulthood. These two environments could not be more different. The safe and nutritive environment of the womb predictably yields to the more hostile existence of life after birth. Nevertheless, the relatively short prenatal existence has always held a fascination for us as we marvel at the apparent recapitulation of our developmental history. Advances in scientific understanding now are at the point where the homunculus of our ancestors' imaginations has given way to an appreciation of the intricate patterning faithfully reproduced by our genetic blueprint. Our ability to intervene prenatally when nature's course deviates has long been limited to the physician's crude palpations and auscultations, methods woefully inadequate to diagnose, let alone treat, fetal problems. Only through persistent scientific inquiry, driven by our inherent curiosity about our development, have we now reached the threshold of prenatal diagnosis and treatment necessary to ensure the mother's safety or save an endangered life. The fetus, once a captive of its own environment, an enigma to be protected but left untreated, finally has gained the status of patient. Accordingly, fetal research itself enters an important new era. In this article, we review some of the significant contributions of fetal research and fetal tissue research over the past 20 years. It is important to draw a distinction between fetal research, that is, research performed on the living fetus in utero, versus fetal tissue research that focuses on tissues or cells derived from the dead fetus, obtained as a result of spontaneous or induced abortion [1]. By its very nature, scientific inquiry that involves fetal research or the use of fetal tissues often is obscured in the larger ethical, moral, and legal questions surrounding the use of fetuses, especially human fetuses, in research of any kind. These concerns are not trivial, for they strike at the heart of our moral dilemma regarding abortion, or the use of invasive procedures on a patient (the fetus) who can neither be informed nor grant consent. The resolution of these concerns and the answers to the ethical and legal questions will require honest, open dialogue from all aspects of society before, and if, a consensus is ever forthcoming. Our intent is not to debate whether fetal reseach should continue; rather, our focus will be on why fetal research and fetal tissue research are done at all, what procedures are feasible, and how this research benefits mankind. Prenatal Diagnosis Fetal research plays a vital role in the continued ability to diagnose a variety of fetal disorders, from genetic inborn errors in metabolism to congenital malformations (Table 1). Approximately 150,000 children in the United States alone, representing 3 to 5% of all live births each year, are born with congenital abnormalities [2]. Ultrasonography, a noninvasive procedure that permits visualization of the fetus without apparent risk to fetus or mother, is one of the most important diagnostic advances available to the physician [3] and is used as an aid for the accurate guidance of instruments. Ultrasonography is also used to assess fetal movements and gross fetal malformations. For example, neurological defects such as anencephaly, spina bifida, and hydrocephalus can be diagnosed with ultrasonography. Heart defects, which occur on the order of 1% of all live births [4], and various obstructive disorders of the gastrointestinal or urinary tracts also may be visualized with this noninvasive approach. In contrast, early diagnosis of inherited chromosomal abnormalities, fetal disease, and metabolic deficiencies require invasive intervention. Amniocentesis, the withdrawal of amniotic fluid, has dramatically changed the physician's ability to diagnose, counsel, and implement treatment [5]. The assessment of chromosomal abnormalities, amniotic infections, fetal lung maturation, and the severity of hemolytic disease related to Rhesus (Rh) factors is now possible; however, most amniocentesis is used for cytogenetic studies [6]. In addition to direct chromosomal analysis, recombinant DNA technology now makes it possible to diagnose a large number of genetic disorders. Presently, more than 4000 disorders in man are known or suspected of being due to a single gene mutation, and as many as 300 gene mutations in humans may be X-linked [7, 8]. By means of recombinant technology, many gene mutations may be identified either directly or with the use of restriction fragment length polymorphisms (RFLP). Disorders such as Huntington's disease, Duchenne muscular dystrophy, sickle cell anemia, hemophilia, and cystic fibrosis have been diagnosed by the use of RFLP. Inborn errors in metabolism also may be assessed by culturing fetal cells suspended in the amniotic fluid sample and subjecting their resulting gene products to enzyme analysis assays. Although prenatal diagnosis of most inborn errors or metabolism are made by analyzing the gene product, several direct determinations of unique metabolites in the amniotic fluid sample are also possible [9]. For example, hexosaminidase A, the deficient enzyme of the autosomal recessive disorder Tay-Sachs disease, can be diagnosed directly [10]. Endocrine disorders such as adrenogenital syndrome are diagnosed during the prenatal period by direct assay for the elevated levels of 17[alpha]-hydroxyprogesterone in amniotic fluid [5]. Amniocentesis also is a vital diagnostic procedure for the detection of neural tube defects, such as spina bifida, encephalocele, and anencephaly. These neural tube defects, for example, affect about 1 to 2 in 1000 liveborn infants in the United States and Canada [6]. These defects result from the failure of the embryonic neural tube to close, and their diagnosis relies on the determination of elevated levels of [alpha]-fetoprotein, a glycoprotein normally found in fetal serum [9]. The [alpha]-fetoprotein leaks through the membrane covering such neural tube defects and accumulates in the amniotic fluid and maternal serum [6]. One significant drawback of amniocentesis is that it usually is not performed before 15 to 16 weeks gestation, and any final diagnosis dependent on cell culture must be delayed an additional 2 to 3 weeks [3, 6, 9]. Moreover, the rate of pregnancy loss relating to amniocentesis is approximately 0.5% in the United States [11]. Earlier diagnosis of chromosomal abnormalities is possible by using ultrasound-guided chorionic villus sampling, which may be performed as early as 8 weeks gestation. Chorionic villus sampling, although valuable for gathering karyotyping data at earlier gestational ages, does pose a slightly higher risk of fetal loss than amniocentesis [12]. Fetoscopy, that is, percutaneous transabdominal uterine endoscopy, provides additional advantages for prenatal diagnosis. Anatomical malformations may be directly visualized, and fetoscopy may be used to obtain blood or tissue biopsy samples [6, 9]. Since 1983, a newer sampling procedure for obtaining fetal blood samples, called percutaneous umbilical blood sampling (PUBS), has proved valuable for diagnosing fetal hemolytic disease and a number of genetic disorders [13]. During PUBS, an ultrasonographically guided needle is inserted directly into an umbilical vessel to withdraw a fetal blood sample. The procedure may be performed on an outpatient basis, does not require maternal sedation, and is safer for the fetus than fetoscopy [13]. Nevertheless, PUBS is still considered an experimental procedure and should only be performed at selected medical centers [13]. Procedures that involve collecting amniotic fluid, blood, urine, or other body fluids are used to diagnose almost 100 genetic diseases that result from single gene mutations [8]. Tissue biopsies are especially valuable in prenatal diagnoses when chorionic villus sampling or amniocentesis results are equivocal, and for gathering information about multifactorial inherited congenital anomalies not easily or readily diagnosed by chromosomal or biochemical abnormalities present in the amniotic or other fetal fluid samples (Table 2). Diagnostic procedures such as those described above are possible because of technical advances developed from fetal research. Refinements of these procedures are first developed in suitable lamb or nonhuman primate animal models and then judiciously introduced into the clinical setting [9]. Additionally, a number of biopsy procedures are being developed and perfected. For example, blood, skin, or liver may be biopsied by the use of fetoscopy. About 100 enzyme deficiency disorders can be diagnosed rom cultured fibroblasts, and another 100 deficiencies are diagnosed from specific cell types obtained from fetal tissue biopsies [8]. However, before these invasive procedures become standard clinical practice, they must be carefully tested for their safety and effectiveness in clinical volunteers. To illustrate this point, some enzyme deficiencies can only be diagnosed from fetal liver cells. Needle biopsies of the fetal liver are possible, but questions concerning liver damage, intraperitoneal bleeding, or fetal injury surround this procedure. The answers to these questions were obtained by experimenting with fetal liver biopsy procedures on fetuses of patients undergoing second-trimester abortions [9]. The biopsy procedures were successful. Consequently, enzyme deficiencies such as glucose-6-phosphate deficiency, which occurs in von Gierke's disease and is related to the liver's ability to store glycogen, may now be diagnosed [9]. Similarly, several rare enzyme deficiencies of the urea cycle, for example, carbamyl-phosphate synthetase and ornithine transcarbamylase, may be diagnosed from fetal liver biopsies [14]. Research on the fetus is essential before diagnosed disorders can be treated. The efficacy of vaccines, such as the rubella vaccine for the prevention of German measles, or the titration of drugs can only be tested in pregnant women. The fetus is not an innocent bystander if maternal treatment necessitates medical intervention. Virtually all commonly used drugs with the possible exception of insulin, heparin, dextrose, and thyroxine pass through the placenta to varying degrees [15]. Therefore, the safety of medications such as hormones, diuretics, anticonvulsants, anesthetics, and analgesics must be tested first in utero to determine their effect on the fetus. Moreover, fetal disorders such as cardiac arrhythmias are responsive to antiarrhythmic drugs such as digitalis and may be treated directly while in utero [9, 16]. In instances where substances do not cross the placenta, or do so poorly and at low levels, medications or nutritional supplements may be administered directly into the amniotic fluid where oral ingestion and gastrointestinal absorption by the fetus can occur. Surgical Intervention For those disorders affecting a single organ system or resulting from an isolated congenital malformation, unencumbered by multifactorially inherited abnormalities, surgical intervention may provide the most promising prognosis. Obstructive hydrocephalus and urethral obstruction are among several anatomical malformations amenable to surgical intervention in utero. Obstructive hydrocephalus, a condition that occurs with an incidence of about 5 to 25 per 10,000 births and is characterized by dilation of the brain's ventricular system due to the obstruction of the normal cerebrospinal fluid (CSF) pathways, leads to significant brain compression and neurologic dysfunction. The surgical insertion of a ventriculoamniotic shunt with a one-way valve that permits the release of CSF into the maniotic fluid offers one possibility for decompressing the brain [17]. Obstructive uropathy and the resulting damage to the developing kidney also may be corrected by the surgical placement of a suprapubic drainage catheter. The catheter is guided into the distended fetal urinary bladder by the aid of sonography, and the accumulated urine is drained into the amniotic fluid [18]. These surgical procedures, and others still under development, were made possible because suitable animal models were available [19]. This experimentation is d
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