Professional Ethics Report Publication of the American Association for the Advancement of Science (AAAS), Scientific Freedom, Responsibility & Law Program, in collaboration with the AAAS Committee on Scientific Freedom & Responsibility VOLUME XXIII NUMBER 2 SPRING 2010 THE COMING REVOLUTION IN shares with the woman carrying it. to a previously untapped source of fetal PRENATAL GENETIC TESTING Obtaining DNA from this protected DNA. source has required invasive methods. Henry T. Greely and Jaime S. King Scientists have known for many years Amniocentesis, the most common that fetal DNA leaks into the maternal Greely is the Deane F. and Kate Edelman method, pokes a needle through the blood stream through the placenta, Johnson Professor of Law and a pregnant woman’s abdomen at 16 to 20 usually in the form of whole fetal cells. Professor, by courtesy, of Genetics at weeks of pregnancy to withdraw Detecting such cells is difficult, but Stanford University. King is an amniotic fluid containing fetal cells. possible. Testing them for fetal DNA, Associate Professor at the Hastings Another method, chorionic villus however, is complicated by the fact that College of Law. Correspondence should sampling (CVS), is performed at 10 to 12 many women still have some cells in be addressed to Greely at weeks, usually by snaking a catheter their blood derived from earlier [email protected]. through the vagina and the cervix to pregnancies. Finding the fetal cell retrieve a bit of placenta. Both methods At least since the 1932 publication of needles in the haystack of a pregnant are expensive and uncomfortable; both Brave New World, our society has woman’s blood will not be helpful if they increase the risks of miscarriage for the worried about the possibility of someone are not from the current pregnancy. fetus by about one-half to one percentage selecting the next generation based on its point. Improvements in non-invasive But blood also contains a great deal of genes. Prospective parents have had the ways to screen for Down syndrome and cell-free DNA (“cfDNA”), DNA that has opportunity to do prenatal genetic testing neural tube defects have led to the decline been released by the death of cells and for over forty years, and yet the Brave in the number of women seeking invasive then chopped up by blood-borne enzymes New World has not appeared. prenatal genetic testing. into fragments about 100 base pairs long. Of the roughly 5.2 million American We all have large quantities of cfDNA Another way to get a potential child’s women who were pregnant in 2009, only circulating in our own blood. Pregnant DNA is through preimplantation genetic about 60,000 – just over 1 percent – women, though, have cfDNA not only diagnosis (PGD), which allows obtained some form of prenatal genetic from their own cells but from fetal cells. prospective parents to select embryos for diagnosis. The mystery of why so few Within the first few weeks of a transfer to the uterus based on genetic women get this testing is not hard to pregnancy, five to ten percent of the characteristics. This method can be done solve – the testing is expensive, cfDNA in a pregnant woman’s blood only with in vitro fertilization, where the uncomfortable, and carries risks. That serum is from the current fetus. After embryo is easily accessible rather than may soon change. If it changes as we delivery or termination, cfDNA from the hidden somewhere in the Fallopian tubes expect, millions of women will receive fetus disappears from the woman’s or uterus. A few thousand babies are this kind of testing every year, a system within 24 hours, eliminating any born in the United States each year after quantitative change that will force our question regarding the origin of any non- PGD. But, of course, in vitro fertilization societies to face questions that we have maternal DNA. with PGD is even more expensive, been able until now to ignore. uncomfortable, and risky to the mother Several academic researchers (and Prenatal Testing, Today and than amniocentesis or CVS – and its several companies) are trying to develop Tomorrow chances of producing a baby are limited. useful genetic tests from fetal cfDNA. Professor Steve Quake at Stanford is Current reproductive genetic testing So we can test the genetic make-up of the exploiting the sharply reduced cost of methods can be divided into two next generation, but, for reasons of cost, DNA sequencing to examine by shotgun categories – prenatal and preimplantation. discomfort, and risk, we rarely do it. sequencing all the cfDNA in 7 to 15 Prenatal genetic diagnosis requires DNA This is about to change – and with it may milliliters of pregnant woman’s blood from the fetus, but the fetus is carefully change the future of human reproduction. serum. Roughly 90 percent of the DNA insulated from the outside world, floating Change is coming because of a will be from the woman, but the other 10 aloof and apart in its amniotic sac, its technological advance that permits access percent or so will be from the fetus. By only connection through the placenta it counting matching sequences, he expects Spring 2010 Professional Ethics Report 1 to be able to determine reliably which trisomies already demonstrated, but • How widely would the technique be bits of sequence are from the pregnant variations in the sex chromosomes. used? woman alone and which are from the Determining fetal sex is almost trivially • Who is going to talk to patients fetus. In a 2008 study, Quake easy. about it and how? demonstrated the effectiveness of his Whether and how well the method can • Who will pay for it? approach in ascertaining aneuploid work beyond counting chromosomes • What will the effects be? fetuses (those not bearing the usual 46 remains to be seen. Quake believes that • What will, and can, the law do? chromosomes), by accurately he can detect several megabases of • What should we, as a society, do? distinguishing between nine fetuses with genomic sequence, picking out those that trisomy 21 (Down syndrome), two with In general, the social and ethical may be of particular interest to potential trisomy 18 (Edward syndrome), one with challenges raised by fetal cfDNA testing parents, such as the common pathogenic trisomy 13 (Patau syndrome), and six differ in degree rather than in kind from alleles in Mendelian diseases – or, with the normal number of chromosomes those raised by current reproductive perhaps, the whole sequence for the [1]. genetic testing techniques. exons and other sensitive regions of the The Conference genes involved in those diseases. No The first three areas were all linked to obvious barrier exists, but the accuracy of each other and to the effectiveness and On May 7, 2010, the Stanford Center for such a method (and, perhaps, its accuracy cost of the testing. Uptake of testing Law and the Biosciences and the when repeated a second time for critical would likely vary by socioeconomic, Stanford Center for Integrating Research regions) is likely to determine whether religious, education, cultural, and other in Genetics and Ethics sponsored a day- the technique is useful as a diagnostic test characteristics of pregnant women, in long conference at Stanford Law School or as just another screening procedure. ways that might be socially important. to discuss this technology [2]. Variations in who uses genetic testing for Fundamentally, we were interested in two The answer will make a huge difference reproductive selection can further stratify questions. First, does this seem likely to in the technique’s use. Another blood- socioeconomic groups across not just work (and, if so, how well)? Second, based screen for aneuploidies will spark wealth lines, but also in their what would be the social and ethical only limited interest; a non-invasive predisposition to disease and undesirable implications if it did? diagnostic test for aneuplodies would genetic traits. Less obviously, but ignite more. For Mendelian diseases and As to the first question, the conference equally importantly, uptake would also traits, a non-invasive screening would did not bring to light any reasons to vary by the nature of the communication likely find substantial interest, but a non- believe some version of this method and consent process. If women just invasive diagnostic test would probably would not work. The reduced cost of receive one more form to sign, be revolutionary. DNA sequencing makes it possible to authorizing more tests on yet another sequence as many tags as necessary to The bulk of the conference considered blood draw, many may be shocked later illuminate the relevant sections of the this last possibility. We assumed that to find that they had authorized genetic fetus’s genome. Aneuploidies are clearly non-invasive cfDNA testing could testing of the fetus. The conference discoverable, including not only the three provide diagnostic information about reached a consensus around the need to aneuploidies and roughly 100 Mendelian educate both pregnant women and the Editor: Mark S. Frankel diseases or traits without needing follow- general population about the implications Deputy Editor: Nicole Carlozo up by amniocentesis or CVS needed. of all forms of genetic testing. Providing Contributing Authors: Nicole Carlozo, This hypothetical test would require 10 good counseling for millions of women a Rebecca Carlson, Erin Heath, Anna Ing, milliliters of blood from the pregnant year will be extremely challenging. Jordan Johnson, Emil Kiner, Lindsay Pascal woman, could be performed as early as Who will pay will also be important. At the fifth week after the last menstrual the stipulated $1,000 per test, some The Professional Ethics Report is period, and would cost about $1,000. If published quarterly by the Scientific people might choose to pay for it so, we asked, “What happens?” Freedom, Responsibility and Law Program themselves, but far more, no doubt, in collaboration with the Committee on The Implications would opt for the test if it were covered Scientific Freedom and Responsibility.