Tag Archives: history of genetics

Imperfect Pregnancies: What Ilana Löwy Has To Tell Us About The History of Prenatal Testing

“It seems to me that all the gentlemen agree, some more explicitly than others, that to abort is a good thing and should be encouraged.”
– from a discussion reported in Early Diagnosis of Human Genetic Defects: Scientific and Ethical Considerations, Maureen Harris (ed). National Institutes of Health, 1970.

I sometimes feel like a lone voice howling in the wind-swept darkness when I argue that any opinion, policy, or analysis of prenatal testing must be rooted in historical context. Often these endeavors are informed by technical aspects of a test, such as sensitivity, specificity, cost, and positive predictive value, sometimes accompanied by vague mumblings about “ethical considerations” and “women’s choices.” But these discussions are inadequate unless they also take into account the historical, social, cultural, and economic factors behind the development, expansion, acceptance, and critiques of genetic testing technologies.

To develop a full understanding of prenatal testing, we need to ask difficult questions with thorny, complicated and uncomfortable answers. What was the impetus for the introduction of prenatal diagnosis in the 1960s and 1970s? Why were researchers studying birth defects, cell culturing techniques, and karyotypes at that particular time? How have changing attitudes toward disability, abortion, and reproductive rights shaped, and been shaped by, prenatal diagnosis? What path does a test follow from being offered to a very small and select percentage of the pregnant population to becoming a routine part of every pregnancy? Why are there regional and historical differences in the acceptance, application, and history of prenatal testing? Why is it nearly impossible to have a discussion about prenatal screening that is not also a discussion about abortion?

Well, I don’t feel so lonely anymore after having read Ilana Löwy’s new book, Imperfect Pregnancies: A History of Birth Defects & Prenatal Diagnosis (Johns Hopkins University Press, 2017). The title pretty much tells you what the book is about, but it is more than just a recitation of discoveries and events. The author, an emerita research fellow at the French National Institute of Health and Medical Research, argues that prenatal testing can best be understood in the context of Michel Foucault’s concept of a dispositif – loosely speaking, the institutions, social factors, laws, regulations, scientific and professional practices that create, maintain, and reinforce a body of knowledge and give it power (no doubt some Foucault scholar will take issue with my description, but you get the general idea). But Löwy’s book is not a high falutin’ study of abstract theories of knowledge. It is concretely embedded in a richly detailed analysis – some of it original and some of it summarizing the work of others – of how we have arrived at the point where prenatal testing, particularly ultrasonography and now NIPT, has become integrated into the routine care of nearly all pregnant women in many Westernized countries.

Let me acknowledge some intellectual conflicts of interest up front: the author cites some postings to The DNA Exchange by me and others, references some of my publications, and thanks me – among many others – in her introductory section. No doubt these small ego strokes influenced my perceptions of the book in ways that I can’t fully recognize.

Imperfect Pregnancies opens with the somewhat artibitrary but reasonable starting point in the late 19th century and the work of obstetricians John Ballantyne and Adolphe Pinard, in Scotland and France respectively, on the nature and causes of birth defects and the medical supervision of pregnancy that they felt was necessary to ensure the delivery of a healthy baby. From there she ties in the history of cytogenetics and karyotyping, congenital malformations and dysmorphology, the emergence of amniocentesis and prenatal ultrasonography in the 1960s and 1970s, the introduction of serum and sonographic screening for Down syndrome in the 1980s and 1990s, and right up to the  latest testing technologies of the early 21st century such as comparative genomic arrays and noninvasive prenatal testing (NIPT).

This is not a scolding work that draws a straight historical line from eugenics to prenatal diagnosis. While eugenic criticisms are certainly valid concerns about the potential ramifications of prenatal testing and that is true that the development of prenatal diagnosis was a clear reflection of negative attitudes toward disability, the Eugenics Movement per se was not a driving historical engine behind prenatal testing. Still, Löwy makes it clear that prenatal diagnosis was established in the context of a public health model to permit and passively encourage abortion (as the introductory quote at the start of my posting suggests) of aneuploid or otherwise “defective” fetuses under the justification of allowing parents to have as healthy a baby as possible, and that was maintained by the social, ethical, medical, legal, and economic factors that made this possible (i.e., the dispositif). Pregnant women were enticed by tests that offered reassurance but some were left with the messy situation of what to do when the testing did not come back with normal results and had to make extraordinarily difficult decisions about how to proceed in largely uncharted territory, a situation genetic counselors know all too well. In the words of one researcher, women were forced “to become skilled managers of fetal risk.”

The author brings an international perspective to her narrative, including experiences with prenatal testing in the US, the UK, France, Israel, Brazil, and Scandinavia, among others. Prenatal testing is managed differently in each country according to unique local circumstances and this has an impact on uptake of testing and abortion. For example, in the Netherlands, where a detailed discussion of screening is routinely incorporated into pregnancies largely by midwives in a non-medical setting, the uptake of testing is much lower than in countries where there is less discussion and is physician driven. In Brazil, where abortion for fetal indications is limited to anencephaly, the uptake of NIPT is much greater among upper socio-economic status who have access to safe (if technically illegal) abortion compared to poorer women who do not have such ready access. Laboratory marketing has taken advantage of the social status associated with having the latest medical tests among Brazilian women, especially during pregnancy, to further integrate NIPT into routine care. In places around the world where women are likely to leave the work force and devote themselves full-time to child rearing, the uptake of prenatal testing and abortion is lower than in areas where women continue to work after childbirth.

The limitations of the early technologies are somewhat shocking from the biased perspective of today. When John Edwards analyzed the unbanded karyotype of  the first patient with his eponymous syndrome, he thought the underlying cytogenetic abnormality was trisomy 17 rather than trisomy 18 until Klaus Patau (who first described trisomy 13) set him straight. In Riis and Fuchs first reports of prenatal diagnosis of fetal sex among hemophilia carriers in Denmark in 1960, one woman proved to have a female fetus that she miscarried after amniocentesis, went on to have another female fetus that also miscarried after amniocentesis, a third pregnancy that was a male and was aborted, and finally had a fourth pregnancy in which the patient successfully carried the pregnancy to term after a female fetus was correctly identified by amniocentesis (I can envision many prenatal genetic counselors simultaneously nodding and shaking their heads right now). Of the first 20 attempts at identification of fetal sex among hemophilia carriers in Riis and Fuchs series, 17 were successful, two resulted in failure to establish fetal sex, and one female fetus was mistakenly identified as male and the pregnancy was terminated (I can hear many prenatal genetic counselors now saying “Ouch!”).

There are a few areas I think the author leaves largely under-explored. Although she gives thoughtful discussion to genetic counselors, I think she understates their importance in ushering in, shaping, and managing each new prenatal testing technology. We have been the boots on the ground as each test was introduced into clinical practice, more or less left alone with patients to negotiate the complicated medical, ethical, and psychological ramifications of “simple blood tests” and “routine sonograms” gone awry.

In the early sections of the book Löwy details the role that obstetricians played in the historical pathways leading up to prenatal testing. However, there was little mention of the obstetricians who worked closely with clinical geneticists and sometimes became board certified in genetics themselves in the 1970s and 1980s – Mickey Golbus, Larry Karp, Mike Mennuti, and Joe Leigh Simpson, to name a few.

I would also like to have seen fuller discussion of the Professional Liability Alert issued by the American College of Obstetricians and Gynecologists in May of 1985, which stated: It is now imperative that you investigate the availability of these tests in your area and familiarize yourself with the procedure, location, and mechanism of the follow-up tests to screen for neural tube defects. Although to the best of my knowledge no one has ever studied the impact of this Alert on the uptake of maternal serum screening in the US, I know that the immediate  impact in my neck of the woods was profound and long-lasting. Most of the obstetrical care providers in the Seattle area suddenly started strongly recommending AFP screening to their patients and it set the tone for the ready acceptance of most other prenatal screening tests that followed over the next 30 years. Although the book briefly mentions obstetricians’ concerns about legal liability, she does not go further down this street and I believe incorrectly attributes it to the AMA’s “concerns.”

But these latter points do not detract from the overall achievements and arguments of Imperfect Pregnancies. If you are a supporter or a critic of prenatal testing, or, like many people, decidedly ambiguous, there is much that you will learn and much that will make you pause and re-examine your own views and knowledge base.


NEWS FROM AROUND THE DNA EXCHANGESupport The Genetics Literary Community

I am delighted and excited to announce that The DNA Ex’s own Laura Hercher is now also contributing an online column for Genome magazine called GenomeCulture. Read her first installment When Genetics Race Problems Rears Its Ugly Head.

Tony Holzman, now retired from Johns Hopkins and who contributed so much valuable research on the social, ethical, and psychological aspects of genetics, is now a novelist. He has published several novels including Blame, about murder and intrigue in genetics research at the NIH. Tony is now working on publishing his newest novel, The Bethune Murals. The novel is based on the true life story of a physician who was diagnosed with TB and was confined to the Trudeau Sanitarium in the 1920s and who produced a remarkable set of murals on paper used to wrap laundry at the institution. Tony is looking to self published his book through Amazon but needs to get enough votes in an Amazon competition. If you have an Amazon account, you can vote for Tony here.

 

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What Did You Do This Summer (Genetics Edition)?

As the summer of 2012 starts to fade into cooler evenings, I have been wondering  – like so many summers before – just where it went and how come I did not accomplish any of the tasks I had so confidently laid out for myself back in early June. When I was a boy, on the last day of school summer would open up before me like a vast ocean of free time and then, in the blink of an eye, it was Labor Day and the seas of time had been transformed into a dripping spout of precious minutes. This got me me to thinking  about the history of genetics.  Are summer’s creative doldrums my peculiar affliction? What have other geneticists done during their summers? To satisfy my curiosity, I compiled a list of summer time achievements and events from the history of genetics, culled from my unorganized and arbitrary historical knowledge.

The most important doodle in the history of ideas in the Western world, here displayed on my iPhone cover (made by my talented daughter Emily Singh). The image is modified from the classic image in Darwin’s Notebook D, Transmutation of species (1837-1838) and is the first graphic expression of his branching species theory of evolution. Just above this doodle, Darwin wrote “I think.”

July 1, 1858: The theory of evolution was inconspicuously introduced to the world when the joint papers of Charles Darwin and Alfred Russell Wallace (On the tendency of species to form varieties; and on the perpetuation of varieties and species by natural means of selection) were read to about 30 members of the Linnean Society in

London. By all accounts, the papers generated virtually no discussion. Not even a Tweet. Neither Darwin nor Wallace were in attendance. Wallace, who may be the only Englishman unluckier than Pete Best (who was fired as the Beatles’ drummer in the summer of 1962) was off in New Guinea seeking birds of paradise. Darwin was grieving the death of his beloved tenth child, 19 month old Charles Waring Darwin, who very well may have had Down syndrome.

September 2, 1939: German U-boats torpedoed SS Athenia, the first British ship sunk during WWII. More than one thousand survivors were plucked from the icy North Atlantic waters, including Charles Cotterman, who 10 years later would become the founding editor of The American Journal of Human Genetics and the designer of the journal’s original cover (as told in The Science of Human Perfection, my friend Nathaniel Comfort‘s soon to be published book on the history of medical genetics). Ironically, on board the rescue ship City of Flint was one James V. Neel, the great geneticist and founder of the Heredity Clinic at the University of Michigan where Neel and Cotterman collaborated during the 1940s. The summer of 1939 also saw Cuba and the US deny entry to a thousand Jewish refugees aboard the the SS St. Louis, who had escaped the Nazi horrors only to be sent back to Europe. One of the passengers on board was a teenage Arno Motulsky, who would later found the medical genetics department at the University of Washington, and author a classic human genetics textbook and numerous research papers. The story of the SS St. Louis was later told in both film and book as The Voyage of the Damned.

August, 1947Sheldon Reed succeeded Clarence Oliver as the director of the Dight Institute of Human Genetics at the University of Minnesota. The rest is genetic counseling history.

July 15, 1949: James Neel published his classic paper The Inheritance of Sickle Cell Anemia in Science (actually, the inheritance of sickle cell anemia was first reported 26 years earlier by W. H. Tallifero and J.G. Huck).

July 6, 1957; August 3, 1957; August 30, 1958: R.A. Fisher, the great statistical geneticist and one of the leading architects of the modern theory of evolution published 3 papers (in The British Medical Journal and Nature) claiming that cigarette smoking and lung cancer were genetically linked (“… an error has been made of an old kind, in arguing from correlation to causation”). Fisher’s arguments formed a key component to the tobacco industry’s strategy to deny the health risks of cigarettes. Fisher was paid a small fee to serve as a scientific consultant for the Tobacco Manufacturers’ Standing Committee.  He wrote the papers in response to a paper authored by the British Medical Research Counsel in Lancet in June of 1957 that stated that the recent increases in lung cancer could be largely attributed to cigarette smoking. Fisher strongly denied that the money he was paid could possibly influence his views. Talk about blind spots.

August 20-27, 1958: Jérôme Lejeune first reported the underlying chromosomal basis of Down syndrome at the X [tenth] International Congress of Genetics at McGill University in Montreal. The finding was published 4 months later in January, 1959.

June 26, 2000: US President Bill Clinton and British Prime Minister Tony Blair jointly announced the completion of the first draft of the human genome.

Well, I guess I don’t have the excuse that geneticists never do anything important during their summers. Next year I will have to get more serious about pursuing my genetic exploits. But, hey, I have nine more months to ponder that.

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L’histoire de p et q: Urban Myths of Cytogenetics

Karyotypes are sooooo 20th century. Time was when a ripe crop of G-banded chromosomes promised a fruitful harvest of genetic secrets. But nowadays a Giemsa-stained karyotype seems like a quaint low resolution black and white TV set – those cute little D & G groups even have rabbit-ear antennas – compared with the bright, sexy colors of FISH, the fine oligonucleotide detail of microarrays, and the dense volumes of data of generated by high throughput DNA sequencing.

But before all that trypsin, calf serum, and Giemsa stain sails off in a T-25 culture flask to navigate the seas of our mythic memories, some cytogenetic stories need to be told. The tale I want to relate started with an email from Debbie Collins, one of our Kansas City genetic counseling colleagues.

“I went to a lecture today,” Debbie’s email began, “and learned how the chromosome’s short and long arms came to be called p & q.” She then related a story that was completely different than what I had always held to be true.

Debbie’s email got me into a Rudyard Kipling frame of mind. Just how did the chromosome get its name? As it turns out, probably neither Debbie’s story nor my story is true. I searched for the “real” answer in standard genetics textbooks and PubMed, but to no avail. So I unscientifically queried geneticists and cytogeneticists of various stripes and ages about how they thought “p” & “q” came to be the official chromosomal designations. Here are their stories, with annotations by me:

1)    The French Connection. This was the most popular version in my unofficial survey.  In this story, “p” stands for petite, the French word for “short.” The long arm came to be called “q” because “q” follows “p” in the alphabet. But that seems inconsistent. Why would one chromosomal arm be named after a word and the other arm named after a letter? It would be more logical to call the long arm “g” for grande, French for “big” or “large.”

2)    Francophones vs. Anglophones. In this version, the French in fact wanted to go avec “p” et “g”. Mais l’English speaking contingent objected to the French conquering the entire chromosome, apparently still harboring some nationalistic resentment nine centuries after The Norman Conquest. The Anglophones held out for “q” because, they claimed, “q” follows “p” (see The French Connection above). But really “q” appears English and also had the quality of making “p” evoke English rather than French. Even though it gave the appearance of a civilized linguistic compromise in which both sides got to name half of a chromosome, victoire pour les Anglais. Hastings avenged!

3)    The New York Typesetter’s Error. This is the version Debbie Collins related to me. The 1971 Paris conferees recommended “p” and “g” á la petite et grande. The nomenclature was reported in 1972 in Birth Defects: Original Article Series, which was published in New York City. A mythical typesetter inadvertently confused “g” for “q”.  The mistake was noticed after the issue had gone to press, too late for correction.

Great story, which caters to our stereotypes of New Yorkers’ penchant for giving language a unique twist. Sadly, though, it is not likely true. First off, I’ve never met a cytogeneticist who was not pathologically detail-oriented, and there is no way they would ever let an error like that get beyond the earliest stages. But more tellingly, although the Paris Conference indeed recommended “p” and “q”, these designations were in use at least 5 years before the 1971 meeting.

4)    The Hardy-Weinberg Equilbrium. As one source quoted to me, all geneticists know that p + q = 1. This has nice poetic and historical resonance . But it sounds too pat to be true. Somehow, I can’t imagine a sober-minded committee thinking this up, and then everyone agreeing to it (or perhaps they weren’t sober). Besides, what does cytogenetics have to do with the Hardy-Weinberg Law?

After spending an inordinate amount of time on PubMed, I think that I have narrowed down the start of the p/q story to the Chicago Conference in 1966, also published in Birth Defects: Original Article Series (I have to admit, though, that I have been unable to obtain a copy of this publication. If anybody is willing to send me an electronic or print copy, I would be forever indebted). The 1960 Denver Conference, by the way, makes no reference to “p” & “q.”

Which story do you think is true?  History is essentially the stories about our past that we have come to believe to be true. So let us choose our history systematically and democratically, rather than leaving it to the confabulations of story tellers or the biased views of the powerful. We can create the truth by popular vote, rather than simply relying on bothersome facts. Use the polling box below to vote for your favorite story so we can settle on the official History of Chromosome Nomenclature. Please, no stuffing the ballot box to ensure that your favorite theory wins; I have ways of finding this out and I will hunt you down. It would also be fun to hear other theories that I may have overlooked, so please use the Comments section to add to the list of Urban Legends of Cytogenetics.

See the follow-up to this posting on the DNA Exchange: “p+q = Solved, Being The True Story of How the Chromosome Got Its Name.”

Thanks to Debbie Collins, Alex Minna Stern, and Nathaniel Comfort for helpful discussions.


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Kellogg’s Complaint

Improper kinds of food in the stomach and intestines, will, in this excessively irritable state of the system, cause nocturnal emissions……Farinaecous foods, properly prepared, is incomparably the best aliment for such a sufferer.….

– from A Lecture to Young Men (1838) by Sylvester Graham, Inventor of Graham Crackers

I study the history of genetics because it provides insight into the practice and ethos of genetic counseling. The historical perspective helps me understand why I do what I do. But I also love studying history because of its quirky recesses and unsuspected intersections of historical trajectories. Like  the common thread of eugenics that runs through the histories of masturbation, breakfast cereal, and vasectomy.

Most scholars point to the early 18th century as the beginning of the Western World’s repulsion/fascination with masturbation. In about 1712, an anonymous author published a pamphlet titled Onania; or The Heinous Sin of Self Pollution and all its Frightful Consequences, in both SEXES Considered …. (the title goes on for another 30 words or so) that describes the physical and psychological toll taken on those who engaged in what was politely called “the solitary vice,” as well as advice on how to treat the newly-minted medical condition.  Onania appeared in multiple editions throughout Europe and the United States. Over the next two centuries numerous similar publications followed , all  variations on the same theme, i.e. men and women needed to be saved from the debilitating effects of this evil practice (WARNING: This video link is somewhat risqué).

Some of the great minds of Western history weighed in on self-stimulation, such as Immanuel Kant (he is the father of autonomy, after all), Jean-Jacques Rousseau, and of course Sigmund Freud. Richard Wagner, the great German composer and anti-Semite, foreshadowed future connections between eugenics and masturbation when he blamed the degeneracy of Jews on their supposed frequent practice of “self-pollution.” Some authors recommended extreme physical measures to prevent masturbation (WARNING: this link is not for the weak of heart or those who might be offended by unusual paraphernalia). Christine O’Donnell is just one of the lesser lights in a long and eclectic line of anti-masturbationists.

In America, one of the most committed anti-masturbationists was John Harvey Kellogg, a respected surgeon who believed that a vegetarian diet and vigorous exercise promoted physical and emotional health. Kellogg was particularly concerned that sex, including sexual relations between husband and wife , was detrimental to health and well-being (all of his 42 children were adopted or foster. He and his wife slept in separate bedrooms and proudly spoke of their lack of a sexual relationship). The most debilitating sexual behavior was masturbation, which, according to Kellogg,  could be identified by any of 39 signs such as general debility, early signs of consumption, premature and defective development, failure of mental capacity, love of solitude, unnatural boldness, mock piety, paralysis, and eating clay, slate pencils, plaster, and chalk.

For Kellogg, the solution to the masturbation problem was simple – a healthy diet and active lifestyle.  Kellogg concocted various foods with the aim of promoting health and preventing masturbation. Granola was one of his earlier attempts. Eventually, Kellogg, along with his brother Will, developed what they felt was the perfect health food – flaked dry cereal, what we know today as Kellogg’s Cornflakes. The Kellogg brothers served cornflakes at their exclusive Sanitarium in Battle Creek to well-heeled clients  – along with a daily serving of yogurt administered to both ends of their clients’ digestive tracts. One bowl of cornflakes in the morning and Voila!  not only will you be healthy, you will become master of your own domain.

Concerned as he was with individual purity, it is not surprising that Kellogg was interested in racial purity. In 1906 (the same year his brother Will founded what would eventually become the Kellogg Cereal company), he established the Race Betterment Foundation in Battle Creek. The Foundation, one of the key eugenic centers in the United States, sponsored 3 conferences on race betterment, collected eugenic family histories, and worked with other eugenics organizations around the country.

From here the story heads south to the state reformatory for youthful offenders in Jeffersonville, Indiana where Dr. Harry Sharp presided as the institution’s medical superintendent. The aptly named Dr. Sharp is generally regarded as the father of vasectomy. Sharp honed his surgical skills on the reformatory’s young men among whom masturbation was presumably a common occurrence, a behavior that did not sit well with the medical superintendent. As Sharp tells it “…the story of my first operation in October, 1899. A boy 19 years old came to me and asked he be castrated, as he could not resist the desire to masturbate….I did the operation [vasectomy, not castration]…..In two month’s time he came to me and told me he had ceased to masturbate and that he was all right… Three months after that operation he made satisfactory advances in the school. This was true practically of every man operated on; every man who has ceased to masturbate has assigned the same reason: practically every man sleeps better, feels better and has a better appetite.” Sharp went on to perform another 175 vasectomies between 1899 and 1907 “solely for the purpose of relief from the habit of masturbation.”

Sharp, like many of his contemporaries, became interested in eugenics.  From his viewpoint in a penal institution, he saw a world overcrowded with indiscriminately breeding mental and physical defectives: “The class of individuals is very prolific, from the fact that in the matter of sexuality, as in everything else, they know of no self-restraint. They indulge their selfish lust, ab libitum, with no thought whatsoever  as to what the result may be…..They simply know that they want gratification, and gratification they are going to have.” Sharp wanted to curtail reproduction among those with defective germ plasm.  After dismissing alternative approaches like marriage restriction laws, castration, and segregation, he championed vasectomy  as the cure for eugenic degradation because, in his view, the procedure was quick and easy to perform, had no serious side effects, did not hamper a man’s pursuit of life, liberty or happiness, and “it is endorsed by the persons subjected to it.” Sharp performed 456 eugenic vasectomies between 1899 and 1908. Note that Indiana did not enact a mandatory sterilization law until 1907; in 1909, Indiana governor Thomas Marhsall ordered a moratorium on sterilizations (In an odd historical connection to another well-known consumer products company, the reformatory eventually became a factory for Colgate-Palmolive).

It is easy to dismiss Kellogg as a, well, flake, and Sharp as a narrow-minded crank. Yet in many ways society has benefited from both men (though not in the ways they intended). Neither man fits neatly into labels like eugenicist or eccentric. They were complex men who were  products of their complicated times. Eugenics, anti-masturbation preaching, health foods, and vasectomy were all “in the air” in the late 19th century, and it is not surprising that their paths should criss-cross.

There is an ironic modern twist to the end of this tale. The state of Washington recently enacted legislation granting licensure to genetic counselors. In completing my license application, I was required to affirm that I have never been convicted of “frotteurism.”  I have never been accused or convicted of any crime but I could not honestly answer the question because I didn’t know the meaning of frotteurism, so I looked it up: the practice of touching or rubbing against the clothed body of another person in a crowd as a means of obtaining sexual gratification. All those bowls of cornflakes and graham crackers from my childhood finally paid off.

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