Having It All*
2007; Elsevier BV; Volume: 81; Issue: 4 Linguagem: Inglês
10.1086/521405
ISSN1537-6605
Autores Tópico(s)Prenatal Screening and Diagnostics
ResumoWhen I first learned that I was to give this talk, I looked back at my predecessors to see what they had done. I found basically three prototypes: first, the straightforward scientific talk on the subject of one’s work; second, the philosophical talk that tries to either interpret the past or predict the future of genetics; and third, the autobiographical talk that discusses the processes that shaped one’s own career. Being bored with the first and not philosophical enough for the second, I have opted for the third. This year marks the 50th anniversary of the first description of the correct human chromosome number.1Tjio J-H Levan A The chromosome number of man.Hereditas. 1956; 42: 1-6Crossref Scopus (556) Google Scholar Although I am sure you all think I remember when the number was 48, I have to disappoint you: I actually do not. However, I do remember when we didn’t know that Down syndrome was the result of an extra chromosome. Diagnosis of a newborn often involved something called “dermatoglyphics,” where one calculated a Bayesian likelihood that the child had what was then called “Mongolism” by scoring a set of finger and palm print patterns. I hope that my talk will both give the younger folk a feeling for how cytogenetics has progressed in successive stages and also be a nostalgic walk along memory lane for the older folks in the audience. The phrase in my title, “Having It All,” is traditionally used as a description of a lifestyle, implicitly by a woman, that tries to combine career and family life without shortchanging either one. The phrase does apply to my life in the usual sense, and I shall return to this at the end of my talk. However, I chose the phrase because it also seemed to describe my life in human genetics in several other ways. First, cytogenetics has allowed me to combine two seemingly disparate enthusiasms: the part of me that likes to play around in the laboratory with new techniques and the part that likes to sit at my calculator or computer and play around with numbers. Secondly, “Having It All” can also be used as a metaphor for the achievement of the Human Genome Project, which I have also seen come to fruition since attending the first human gene–mapping conference in 1973. Thirdly, I have been able to have it all in another sense, by combining both clinical and research activities during almost 40 years of directing a clinical cytogenetics lab in an academic setting. My father was a chemist, and I owe him much in giving me an early love of science and the expectation that I could excel in it even though I was female. He bought me chemistry sets and other scientific toys, but he had a strict rule that no chemistry experiments were to be done by me without his presence. I suppose as an attempt to make me cautious, he told me stories about the dangers of each compound in my set, what they should not be mixed with, and how they could be used to physically damage either myself or the environment. As a result, he unfortunately instilled in me a fear and dislike of chemistry that persists to this day. I studied biology in college, not only because it was naturally appealing to me because of my love of natural history, but also because it seemed at that time a science fairly free of chemistry. I had discovered I enjoyed mathematics, and part of the appeal of genetics, in which I majored, was that it was a science that dealt in mathematical ratios and experiments that involved counting. I then discovered, under the tutelage of my first mentor, Clarke Fraser at McGill University in Montreal, that there was something called “human genetics” that was even free of experimentation and, at that time, rarely involved labs. This was very attractive to me, and I ended up writing a Ph.D. thesis in human genetics that did not involve ever lifting a pipette but instead dealt with statistical and epidemiological analysis of family data. My problem was that my thesis topic was the role of genetics in spontaneous abortions, and I finished it in 1961, just after the discovery of the first human cytogenetic abnormalities by Lejeune, Jacobs, and others. At that time, we knew nothing about the importance of chromosome abnormalities in embryonic and fetal loss, though, in looking back at the paper published from my thesis, I see that the idea did actually occur to me as a possibility to explain the maternal-age association.It is possible that the effect of parental age is due to an increase in chromosomal aberrations, rather than in genic mutations….[I]n female germ cells…terminalization of chiasmata might increase with maternal age. Terminalization of chiasmata leads to reduced efficiency in pairing of the chromosomes, with subsequent increase in the frequency of nondisjunction. Thus older mothers might have an increased probability of producing gametes with abnormal chromosome complements….2Warburton D Fraser FC Spontaneous abortion risks in man: data from reproductive histories collected in medical genetics unit.Am J Hum Genet. 1964; 16: 1-25PubMed Google Scholar(p17–18) Soon after, Carr in Canada3Carr DH Chromosome studies in spontaneous abortions.Obstet Gynecol. 1965; 26: 308-326PubMed Google Scholar and Szulman in the United States4Szulman AE Chromosomal aberrations in spontaneous human abortions.N Engl J Med. 1965; 272: 811-818Crossref PubMed Scopus (31) Google Scholar first reported the major role that chromosome abnormalities played in causing miscarriages. If I was to continue in this field, I needed to learn cytogenetics. Although Clarke and I did succeed in making the first human chromosome preparations at McGill in 1960, I was still not convinced that the laboratory was a place where I would ever feel at home. In 1963, my husband accepted a job at Barnard College in New York City. I was lucky to find a position in the Department of Obstetrics and Gynecology at Columbia University with Orlando J. Miller (known familiarly as “Jack”), who agreed to teach me cytogenetics and let me work on spontaneous abortions if I wished. I was finally working in a lab and discovered that I enjoyed it. Cytogenetics was much more like cooking than chemistry, and I had always enjoyed cooking. At the time, chromosomes were not banded, and only chromosome groups (A, B, C, D, E, F, and G) could be distinguished reliably. However, it had been discovered that chromosome pairs with similar morphology often replicated asynchronously.5Gilbert CW Muldal S Lajtha LG Rowley J Time-sequence of human chromosome duplication.Nature. 1962; 195: 869-873Crossref PubMed Scopus (72) Google Scholar, 6Morishima A Grumbach MM Taylor JH Asynchronous duplication of human chromosomes and the origin of sex chromatin.Proc Natl Acad Sci USA. 1962; 48: 756-763Crossref PubMed Scopus (111) Google Scholar This could be studied by adding tritiated thymidine to cultured cells at the end of the S phase. Incorporated radioactivity was then detected by dipping metaphase slides in photoemulsion, leaving them for several weeks in the dark, developing the film, and counting silver grains. So, my passion for numbers was to be satisfied again. Jack, his wife, Sandy, Roy Breg, and I had identified a large number of patients with a deletion of a B-group short arm. We showed that the deleted chromosome in patients with features of cri-du-chat syndrome consistently replicated earlier than the deleted chromosome in patients with the features of Wolf-Hirschhorn syndrome. Furthermore, by measuring chromosomes with a map measurer, we showed that the chromosome that replicated earlier was shorter than the one that replicated later. Thus, cri-du-chat could be defined as due to a deletion of the short arm of chromosome 5, and Wolf-Hirschhorn syndrome was due to a deletion of chromosome 4.7Warburton D Miller DA Miller OJ Breg WR de Capoa A Shaw MW Distinction between chromosome 4 and chromosome 5 by replication pattern and length of long and short arms.Am J Hum Genet. 1967; 19: 339-415Google Scholar It was tedious, and, in the end, futile, but it worked. The same process was used to define the deleted large acrocentric chromosome in two patients with a similar phenotype as chromosome 13.8Allderdice PW Davis JG Miller OJ Klinger HP Warburton D Miller DA Allen FH Abrams CAL McGilvray E The 13q-deletion syndrome.Am J Hum Genet. 1969; 21: 499-512PubMed Google Scholar We also used a statistical approach in what was probably the first example of microdeletion analysis.9Warburton D Miller DA Miller OJ Allderdice PW deCapoa A Detection of minute deletions in human karyotypes.Cytogenetics. 1969; 8: 97-108Crossref PubMed Scopus (8) Google Scholar To settle arguments in the lab about whether certain patients really had small deletions of a B-group short arm, we randomized photos of metaphase spreads from these patients, along with positive and negative controls, and had several observers assess which cells had a B-group chromosome with a short-arm deletion. We then tabulated the data by assessor; table 1 is representative of the interesting results. Whereas scorers varied in the number of normal cells they concluded had deletions, they all agreed on which cases had a larger number of cells with a deletion than did normal controls. This “blind cytogeneticist” approach might still be useful when trying to assess those cases, which still occur, when there is argument in the lab about whether some subtle chromosome rearrangement is really present. Of course, these days, we can usually find other more elegant ways to settle such arguments.Table 1.Minute Deletions by Consensus9Warburton D Miller DA Miller OJ Allderdice PW deCapoa A Detection of minute deletions in human karyotypes.Cytogenetics. 1969; 8: 97-108Crossref PubMed Scopus (8) Google ScholarPercentage of Cells Judged to Show a Deletion by ObserverSampleNo. of CellsO.J.M.P.W.A.D.W.D.A.M.Normal8417341121Case 28aStatistically significantly higher than normal control for all observed.7047743364Father of case 287725321631Known deletionaStatistically significantly higher than normal control for all observed.181009494100Note.—O.J.M. is Orlando J. Miller, P.W.A. is Penny W. Allderdice, D.W. is Dorothy Warburton, and D.A.M. is D. Anne Miller.a Statistically significantly higher than normal control for all observed. Open table in a new tab Note.— O.J.M. is Orlando J. Miller, P.W.A. is Penny W. Allderdice, D.W. is Dorothy Warburton, and D.A.M. is D. Anne Miller. After some years of these kinds of heroic efforts to extract more information from unbanded karyotypes, an end of all scientific interest in human cytogenetics was forecast for the first, but not the last, time. Then banding patterns were discovered, and everything changed. Quinacrine banding allowed us, for the first time, to identify all individual chromosome pairs and to detect many more rearrangements. This was essential for the first associations of genes and linkage groups with individual chromosomes and was thus the first step in the Human Genome Project. Banding was first described in 1970.10Caspersson T Zech L Johansson C Modest EJ Identification of human chromosomes by DNA-binding fluorescent agents.Chromosoma. 1970; 30: 215-217Crossref PubMed Scopus (784) Google Scholar By 1973, the first human gene–mapping conference was held at Yale, at which a total of 19 genes were assigned to chromosomes, some of them, as it turned out, incorrectly.11Bergsma D Human gene mapping.New Haven Conference, First International Workshop on Human Gene Mapping: Birth Defects Original Article Series X. National Foundation, New York1974Google Scholar Since, with existing fluorescent microscopic equipment, photographing a Q-banded metaphase might require a 2-min exposure, cytogeneticists all spent a good deal of time sitting in the dark. G banding was thus a major breakthrough. I was fortunate enough to have a super technician, Saundra Villafane, who devised a reliable G-banding method that we quickly adopted in the clinical laboratory. It is now hard to believe, but, at the time, there was an argument among cytogeneticists as to whether Q banding or G banding was better and whether banding needed to be adopted by all labs doing clinical work. Saundra and I were often invited to other labs to demonstrate our banding method. All of you who work in labs (or kitchens) will know that when you perform a technique in someone else’s space, it usually doesn’t work: this was certainly true for our banding method. Nevertheless, I was invited to the Paris Conference on Chromosome Nomenclature, where we drew up the initial banding diagrams. Given the preparations we had to work with, it is impressive that these diagrams were so accurate and useful for so long. The meeting was held at a very undistinguished hotel near Orly Airport, where one could not even go out for a walk in pleasant surroundings. The March of Dimes, who financed the meeting, worked us hard from morning to evening. Here I was, relatively young and in Paris for the first time, but I did not actually see the city until 3 days later when the meeting was over. There were many national and personal rivalries involved in coming to any consensus. For example, the French used R banding, and most of the rest of the world used G banding, so a major problem was to decide which bands had priority in the nomenclature system. Luckily, our chairman, John Evans, who was a very strong-minded Welshman with a booming voice, came up with the brilliant idea that there should not be bands with interbands in between but rather that both dark and light bands should be given equal weight in the numbering system.A band is…part of a chromosome which is clearly distinguishable from its adjacent segments by appearing darker or lighter…. The chromosomes are visualized as consisting of a continuous series of light and dark bands, so that by definition there are no “interbands.”12Paris Conference Standardization in human cytogenetics. National Foundation, New York1972Google Scholar(p6) Otherwise, it might have been even longer before I saw Paris! Banding analysis opened up a whole new continent for exploration, as we identified many new kinds of chromosome aberrations in humans that had previously been shown only in experimental organisms. Larry Shapiro and I described the first human insertion13Shapiro LR Warburton D Interstitial translocation in man.Lancet. 1972; 2: 712-713Abstract PubMed Scopus (13) Google Scholar and also one of the first human dicentric chromosomes, which we showed had only one centromere that remained as a constriction as metaphase proceeded.14Warburton D Firschein IL Miller DA Warburton FE Karyotype of the chimpanzee, Pan troglyodytes, based on measurements and banding pattern: comparison to the human karyotype.Cytogenet Cell Genet. 1973; 12: 453-461Crossref PubMed Scopus (24) Google Scholar Another technical innovation was the discovery, by Joe Gall and Marylou Pardue,15Pardue ML Gall JG Formation and detection of RNA-DNA hybrid molecules in cytological preparations.Proc Natl Acad Sci USA. 1969; 63: 378-383Crossref PubMed Scopus (794) Google Scholar, 16Pardue ML Gall JG Molecular hybridization of radioactive DNA to the DNA of cytological preparations.Proc Natl Acad Sci USA. 1969; 64: 600-604Crossref PubMed Scopus (324) Google Scholar that nucleic acid hybridization would occur on chromosomes fixed on a slide, something not at all intuitively obvious. Kim Atwood, Adjie Henderson, and I set out to apply this for the first time to humans. It was not easy. Recombinant DNA technologies had been banned, so that labeled probe had to be produced by growing cells in the presence of tritiated uridine and by extracting the RNA. Because of the low specific activity of the probes that could be produced, only repetitive sequences could be mapped, and exposure times were at least a month. Again, my statistical inclinations were satisfied, as one had to count the silver grains over all chromosomes and perform statistical analysis in order to distinguish real label from background. How different from the practically instant gratification provided by FISH! In 1972, we published the first localization of human genomic sequences by in situ hybridization,17Henderson AS Warburton D Atwood KC Location of ribosomal DNA in the human chromosome complement.Proc Natl Acad Sci USA. 1972; 69: 3394-3398Crossref PubMed Scopus (453) Google Scholar establishing that the 18–28S ribosomal genes were on the short arms of all the acrocentric chromosomes, as had been suggested much earlier by Malcolm Ferguson-Smith based on other evidence.18Ferguson-Smith MA Handmaker SD The association of satellited chromosomes with specific chromosomal regions in cultured human somatic cells.Ann Hum Genet. 1963; 27: 143-156Crossref PubMed Scopus (43) Google Scholar We also showed that the copy number of these sequences could vary a great deal among chromosomes and that this was associated with behavior, such as satellite associations in metaphase.19Warburton D Henderson AS Atwood KC Variation in the number of genes for rRNA among human acrocentric chromosomes: correlation with frequency of satellite association.Cytogenet Cell Genet. 1976; 17: 221-230Crossref PubMed Scopus (84) Google Scholar We then set out to compare the localization of rDNA in multiple primate species. Since most of these had not been G banded, we had to work out the karyotypes first. Although we wrote one of the first papers comparing the human and chimpanzee G-banded karyotypes, it was turned down by Science because it was “not of general interest.”20Warburton D Henderson AS Shapiro LR Hsu LY A stable human dicentric chromosome tdic(12;14)(p13;p13) including an intercalary satellite region between centromeres.Am J Hum Genet. 1973; 25: 439-445PubMed Google Scholar We did succeed in showing that the rDNA regions in primates had evolved in a rather complex pattern, as illustrated in table 2. No two of the great apes were alike. For example, chromosome 15 contained sites only in the human and orangutan, while only the small acrocentrics contained rDNA sites in the two species of gorilla.21Henderson AS Atwood KC Warburton D Chromosomal distributions of rDNA in Pan paniscus, Gorilla gorilla beringei and Symphalangus syndactylus: comparison to related primates.Chromosoma. 1976; 59: 147-155Crossref PubMed Scopus (34) Google ScholarTable 2.rDNA Sites in the Great ApesHuman HomologueHumanChimpanzeeGorillaOrangutan2p−−−+2q−−−+9−−−+13++−+14++−+15+−−+18−+−+21++++22++++ Total no. of sites5529Note.—A minus sign (−) = no rDNA genes; a plus sign (+) = rDNA genes present. Shaded areas are regions of difference from the human sites. Open table in a new tab Note.— A minus sign (−) = no rDNA genes; a plus sign (+) = rDNA genes present. Shaded areas are regions of difference from the human sites. Meanwhile, I had not forgotten my interest in miscarriages or epidemiology. In the 1970s, I began a collaboration that would last for many years with Dr. Zena Stein, an epidemiologist interested in Down syndrome. Together with Mervyn Susser, Zena and I had the idea that a search for factors influencing the frequency of trisomy 21 could be done much more efficiently by ascertaining all trisomies from a collection of spontaneous abortions. I learned much from my association with colleagues who did real epidemiology, as opposed to my seat-mof-the-pants approach. This included my first exposure to the notion of statistical power: contrary to intuition, it is easier to detect an increase in an entity that occurs commonly than in one that occurs rarely (table 3). To have a 90% chance of observing a doubling of the frequency of trisomy at birth, it would take more than 23,000 births in the exposed and unexposed groups. For the same power, it would take only 893 pregnancies scored as term or miscarriage or 191 karyotyped spontaneous abortions to detect a doubling of the frequency of trisomy at conception. We therefore set out on a 10-year study to examine the role of environmental and other factors in the etiology of aneuploidy and other chromosome aberrations. We ascertained all women having spontaneous abortions in three Manhattan hospitals, karyotyped their fetal tissue, and interviewed women with karyotyped spontaneous abortions, along with an age-matched control of women with live births. To control for recall bias, we used as a secondary control the women with chromosomally normal spontaneous abortions, since women did not know the karyotype of their pregnancy losses at the time of interview. The project director of this study was a graduate student, Jennie Kline, who stayed on at Columbia and has remained my colleague on studies of chromosomes in reproduction ever since.Table 3.Statistical Power in Environmental Monitoring: Detecting a Doubling in the Frequency of TrisomyPrevalence of the Outcome inSample Size (per Group) RequiredaAt α=.05, two-tailed.OutcomeUnexposedExposed80% Power90% PowerDown syndrome in live births.0014.002818,18323,874All trisomies in live births.0033.00667,69310,100Spontaneous abortions in pregnancies.15.21675893Trisomies in karyotyped spontaneous abortions.40.57146191* At α=.05, two-tailed. Open table in a new tab This study was essentially negative, in that it failed to identify any factors associated with chromosome aberrations at conception.22Warburton D Neugut RH Lustenberger A Nicholas AG Kline J Lack of association between spermicide use and trisomy.N Engl J Med. 1987; 317: 478-482Crossref PubMed Scopus (16) Google Scholar, 23Kline J Levin B Silverman J Kinney A Stein Z Susser M Warburton D Caffeine and spontaneous abortion of known karyotype.Epidemiology. 1991; 2: 409-417Crossref PubMed Scopus (42) Google Scholar, 24Kline J Levin B Kinney A Stein Z Susser M Warburton D Cigarette smoking and spontaneous abortion of known karyotype. Precise data but uncertain inferences.Am J Epidemiol. 1995; 141: 417-427PubMed Google Scholar The only consistent positive finding was the association of trisomy with maternal age, which was well known for trisomy 21 but which we could establish was true for most other trisomies as well. At the same time we were doing our study, Pat Jacobs and Terry Hassold were carrying out a very similar study in Hawaii. Many of our analyses benefited from either combining or comparing the two studies.25Hassold T Warburton D Kline J Stein Z The relationship of maternal age and trisomy among trisomic spontaneous abortions.Am J Hum Genet. 1984; 36: 1349-1356PubMed Google Scholar, 26Warburton D Kline J Stein Zk Hutzler M Chin A Hassold T Does the karyotype of a spontaneous abortion predict the karyotype of a subsequent abortion? Evidence from 273 women with two karyotyped spontaneous abortions.Am J Hum Genet. 1987; 41: 465-483PubMed Google Scholar In spite of very different populations in New York City, which included many African Americans and Hispanics, and Hawaii, which included many people of Asian and Hawaiian descent, the frequencies and distribution of anomalies, as well as the maternal-age curves for individual trisomies, were very similar. Both studies, for example, showed a linear curve relating maternal age to trisomy for chromosome 16 and an exponential curve like that for chromosome 21 for most other trisomies. In both studies, trisomy 16 made up about one-third of all trisomic conceptions, and trisomies for chromosomes 1, 11, 17, and 19 were very rare or absent. This was another indication of the general lack of any genetic or environmental factors, except for maternal age, that were associated with aneuploidy. The high rate of chromosomal anomalies in our species seems to be built into our biology and is not usually the result of accumulation of adverse events. Later studies with Jennie Kline have concentrated on the maternal-age relationship. In mammals, all oocytes are created in early fetal life, where they are arrested in meiotic prophase. The first meiotic division is completed only at the time of ovulation. The nature of the change that occurs during this long resting period to cause the increase in error rate in older women is still unknown. We carried out two studies to test the hypothesis that the critical factor was correlated with the age-related reduction in the total oocyte pool or the number of antral follicles recruited per cycle. The first tested this indirectly by comparing age at menopause in women with a trisomic conception and controls.27Kline J Kinney A Levin B Warburton D Trisomic pregnancy and earlier age at menopause.Am J Hum Genet. 2000; 67: 395-404Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar The data appear to support the hypothesis. Women with trisomic spontaneous abortions had a mean age at menopause a year younger than controls. The second study tested the hypothesis more directly by comparing hormonal measures of ovarian age and the number of antral follicles per cycle seen by ultrasound in women with trisomic and chromosomally normal spontaneous abortions. Results were negative with respect to the antral pool size, and there was only a hint, not statistically significant, that the rise in FSH associated with pool size occurred earlier in women with trisomic pregnancies.28Kline JK Kinney A Reuss ML Kelly A Levin B Ferin M Warburton D Trisomic pregnancy and the oocyte pool.Hum Reprod. 2004; 19: 1633-1643Crossref PubMed Scopus (39) Google Scholar Currently, we are studying skewed X inactivation in women with karyotyped losses, following up on data from Wendy Robinson and others, and we plan to re-examine the FSH findings in this sample as well. Meanwhile, on the laboratory front, the Human Genome Project was beginning to take shape. Under one of the first Genome Project grants, my Ph.D. student Steve Gersen and, later, my associate M. T. Yu set out to develop a set of hamster-human hybrids, each of which contained only one selectable human chromosome and was therefore useful for making chromosome-specific libraries and for mapping cloned DNA.29Warburton D Gersen S Yu MT Jackson C Handelin B Houseman D Monochromosomal rodent-human hybrids from microcell fusion of human lymphoblastoid cells containing an inserted dominant selectable marker.Genomics. 1990; 6: 358-366Crossref PubMed Scopus (74) Google Scholar We also developed a chromosome 13–deletion hybrid-mapping panel,30Warburton D Yu MT Tantravahi U Lee C Cayanis E Russo J Fischer SG Regional localization of 32 NotI-HindIII fragments from a human chromosome 13 library by a somatic cell hybrid panel and in situ hybridization.Genomics. 1993; 16: 355-360Crossref PubMed Scopus (10) Google Scholar and I served as the Genome Database Editor for chromosome 13 for many years. Eventually, Columbia became the home of the Genome Center for Chromosome 13, mapping a cosmid library derived from a 13-only hybrid.31Cayanis E Russo JJ Kalachikov S Ye X Park SH Sunjevaric I Bonaldo MF Lawton L Venkatraj VS Schon E et al.High-resolution YAC-cosmid-STS map of human chromosome 13.Genomics. 1998; 47: 26-43Crossref PubMed Scopus (22) Google Scholar Unfortunately, this was one of the several blind alleys taken by the Genome Project, since it was later decided that clones derived from hybrids did not make good sequencing material. Now that we really do “have it all,” we are beginning to reap the benefits. Projects that would have taken years now take weeks. I retain my fascination with new technology and have recently begun collaborating with Michael Wigler at the Cold Spring Harbor Laboratory to use genomic microarray analysis to detect small copy-number changes in the genome. Cytogenetics has entered an exciting era of “ultra high-resolution” chromosome analysis via microarray, which is likely to have as big an impact on human genetics as conventional cytogenetics did in the past. It is likely that a significant proportion of unexplained developmental pathology, as well as variation within normal limits, may be due to such submicroscopic changes. We are currently working on a project to examine copy-number changes in children with congenital heart disease, which again marries epidemiology with new technology. I look forward to an exciting next few years. I will now turn to the third meaning of “Having it All.” This is the opportunity that I have had throughout my career to combine both clinical and research activities. I have been as lucky in my clinical life as I have in my research life, in having many long-time associates who are responsible for making things work. I would like, in particular, to mention Judy Yu, who was my clinical laboratory supervisor for 25 years and continues to work in my research laboratory. My assistant Mary Walsh, whom many of you know on the phone, has been the voice of the laboratory to the world, kept me more or less organized, told me when it was time to get my hair done, and always listened to my problems. My long-time clinical collaborator Kwame Anyane-Yeboa is a marvelous dysmorphologist, always interested in research projects that involve his patients. The opportunity to interact directly with patients, physicians, and genetics counselors has given me great personal satisfaction over the years. While one may see the same cytogenetic abnormality again and again, the personalities and the circumstances involved in each family situation are always different. I have observed the evolution of clinical genetics from a discipline focusing mostly on trying to make the correct diagnosis in order to provide recurrence risks to family members to one where we can offer prenatal and even preimplantation diagnosis for a large number of conditions and effective treatment for a few. I have also seen society change, from a time when children with conditions such as Down syndrome were routinely institutionalized from birth to one tha
Referência(s)