 Thank you very much, Chris. Thank you again for the invitation. It's a real honor to be here, to be giving this inaugural lecture in a series that I hope is extensive and expands for a long time. I think it's a wonderful model for interaction and I'm really happy to be part of it. It's been a real pleasure to meet some of you and hopefully we'll meet some more of you and I'm going to talk a little bit about research from my forthcoming book. It's coming out a little bit later this year on the history of medical genetics and a few sort of projects that I've been working on since then towards my next project. And as historians of medicine often do, I'm going to begin with a very brief story. So in 1967 a one-year-old boy was referred to the Yale New Haven Hospital to investigate the cause of his apparent mental retardation. There he was brought to the attention of the physician and geneticist Herbert Lubs. Now notably for Lubs, this boy's three-year-old brother was also affected with a similar condition. You can see the boys here which involved mental retardation. Lubs was very interested as you can imagine in these brothers. He was working at this time looking at chromosomes more broadly trying to find markers of genetic disease and he saw an opportunity in these brothers to look for a common mutation that perhaps caused their mental retardation among other features. And I want to make a note here upfront about my use of terminology. I'm very sensitive to the stigma associated with the term mental retardation, but I do use my actors categories. In this period mental retardation was the term used by Lubs and by my actors. Other terms like idiocy, mental deficiency have been used in the past, people mindedness and intellectual disability in recent decades. And the reason I use the terms of my actors is because these terms come with, exist within a broader set of assumptions and understandings. If I took a present term like intellectual disability and applied it on the past, I would bring with that our present set of assumptions about this condition. And so I like to use the terms of my actors even though I know that they are difficult and problematic. So the historian Soraya de Chaturavian has argued that during the 1950s and 1960s, chromosomes offered geneticists with an important and a new glimpse of the human genome. And Lubs looked to the chromosomes of these boys. Here is a karyotype he produced for a causative mutation. And in both of these brothers he found one which he thought could be related to their mental retardation. And that was these satellites that you can see here on what Lubs determined to be the X chromosome. As you can imagine at this time it was very hard to actually tell these seven or so chromosomes apart. Lubs looked kind of exactly the same, the C group of chromosomes. And I'll tell you in a minute how he knew it was the X. So Lubs next turned to testing the boys extended family and found that all of the males who possessed this marker were affected with mental retardation, while all of the females who showed it appeared to be clinically normal. So here's a pedigree he produced, the males are squares, females are circles. The two dots means that chromosomal marker, the black bar means mental retardation. We have the two brothers on the bottom here and a couple uncles further up in the family who are similarly affected. And two females, the boys' mother and her sister, who show the marker but do not show this form of mental retardation. Lubs inferred from this, as you probably do as well, that this was an X-link trait. Because males have only one copy of the X chromosome, if they have a mutation it tends to be expressed. Whereas females with that extra copy of the X chromosome, in many cases, do not express the trait. So based on his observations, Lubs described the potential clinical value of this genetic marker, saying, quote, the most immediate medical consequence of these studies has been the opportunity to offer amniocentesis and therapeutic abortion to two women in this family if the marker chromosome is found in a male fetus. Now you'll note this is 1969. This is very early in the days of prenatal chromosomal diagnosis, had only been made possible in the last few years, and of course before Roe vs. Wade by a number of years. Before abortion was in any way legal in almost any U.S. state and certainly not Connecticut at this time. But many hospitals at this time would approve an abortion for therapeutic reasons such as this one. And so he wasn't completely talking without a reality behind him. To my knowledge, neither the woman whose children were affected, or her sister who also showed this marker, ever took him up on this particular offer. So today I want to describe them how Lubs' attempts to identify new genetic disease markers reflected novel ways of managing mental retardation after 1960. Attempts to make one mutation, one disorder links between chromosomes, chromosomal mutations, and clinical outcomes provided the opportunity for prevention via prenatal diagnosis and the option of abortion. Now the case of these two boys comes from my forthcoming book which looks at how conditions like this one were made genetic as part of a chromosomal infrastructure for prenatal diagnosis and prevention. You can see the chromosomes, the banded chromosomal ideograms on the cover there. This is the infrastructure which I traced the history of. I think that it is sort of best represented by Victor McCusick's many diagrams which he called the morbid anatomy of the human genome. For centuries physicians looked to locate the causes of disease within particular parts of the human body. McCusick took that idea and applied it to the chromosomes and the genome, saying we can locate the causes of disease within the human genome and then do something about it perhaps thereafter. And here is just a zoom in on the X. Mental retardation with macro orchidism is the condition that was being described here and you can see that it has been located by the early 1980s within this infrastructure for diagnosis and for potentially prevention. So today I'm also going to describe the more recent direction of my research including my second book. And let me begin by describing the relationship between the two. The second book I'm just beginning the research for. So social conceptions of mental retardation in the late 20th century were shaped by what I would call two countervailing trends. At the same time that the social acceptance and support for disability was on the rise, conditions causing it were increasingly being associated with genetic mutations and thus reduced to pathologies, preventable pathologies potentially. Historians of medicine have examined the role of affected families and government institutions in establishing more inclusive roles of disability since the 1950s. Less attention however has been given to how this influenced physicians approaches to managing disability. So my second book project seeks to examine how more positive and inclusive perceptions of mental retardation entered the medical community after 1970. And my second project is called changing the narrative disability in the late 20th century medicine. And I'll come back to this later but I'm going to be looking at the role of a clinical psychologist named Wolf Wolfensberger who was actually conveniently the University of Nebraska and a particular center called the Monroe Meyer Institute which brings together quite uniquely for its time in the 80s, 90s up to today medical genetics with disability resources. These two things don't usually exist under the same roof but they have had it that way for a while and they have archives and so I'll be looking into that going forward beginning this summer. So today in my talk I'm going to start by looking at the construction delineation, understanding of mental retardation within post-war medical genetics. Then I'm going to look a little bit at some of the new perspectives on mental retardation in society and medicine in the closing decades of the 20th century into the 21st. And finally a little bit on recent more genomic approaches for the prevention of intellectual disability as we now call it among other things. But first I need to begin with even a little bit more historical background going back a little bit further. So throughout the mid-20th century geneticists explored the inherited and environmental basis of what they called mental defect. Most influential among these studies was that of the British geneticist Lionel Penrose, his Colchester survey, which was conducted in the 1930s and data from which was analyzed for decades including by Penrose himself. This is a 1949 book based on in part this data called the Biology of Mental Defect. The 1930s were a time of significant hope that population level genetic studies like this one could lead potentially to the prevention of mental defect. Twenty years later however by the 1950s as the post-World War II era began, geneticists still recognized that they didn't really quite have the knowledge and tools needed to accomplish this. And in the preface to Penrose's book the great biologist J.B.S. Halliday and said, quote, we can't do so much about mental defect as had been hoped in the recent past nor could we do as much about flying 400 years ago as Leonardo da Vinci had hoped. We did not know what data will be required but among them is certainly a great deal of normal human genetics. And indeed it didn't take 400 years for some major breakthroughs to come. Improvements in methods for studying human chromosomes as we know reshaped conceptions of the causes of mental retardation by 1960. And the belief among physicians and geneticists that something could be done to prevent it. And most famous among these is the correlation between trisomy 21 and what was called mongolism in 1969 by Jerome Lejeune. And there were many other examples of this in that time period. Now medical geneticists during this period sought to highlight an active move away. Away from race, class and morality based eugenic thinking of the earlier 20th century towards more discrete markers of diseases, markers like an extra chromosome. Post-war medical genesis acknowledged that all humans and not just certain populations possessed genetic mutations that could cause disease in them or in their children. And Aubrey Malensky who was a pretty active physician and medical geneticist in promoting these ideas and he wrote a popular press book called Know Your Genes in 1977. He said each of us, however healthy, carries at least four to eight harmful genes that we may pass on to our children and grandchildren. This is a warning, a warning that everybody, not just some groups, but everybody is at risk for genetic disease and that everybody in a sense should be tested for their risk factors and aware of those risk factors. Now in the early 20th century mentally deficient patients were primarily categorized by their level of severity from a low grade idiot to a medium grade imbecile up to the higher grade moron. And these terms were common in the medical literature throughout the early 20th century. Whereas in the post-war period mental retardation was more often divided into hundreds of distinct genetic disorders. And this is just one small segment of a table from 1975 of various forms of mental retardation which you note are not characterized at all by their level of severity. They're characterized by the bodily features associated with them. Things like short stature, lung issues, facial issues, eye issues, limb issues. This is how mental retardation was characterized and understood in the post-war period as associated in discrete disorders associated with bodily patterns of malformation. Now we often think of the post-war period as a time in which improving molecular technologies in the laboratory enhanced the ability to treat and to prevent disease. And this is certainly true. Today however I want to argue that the development and diffusion of new approaches for identifying distinct patterns of chromosomal abnormality and bodily malformation were equally important to the successes of genetic medicine. So the years around 1970 were an important organizational period for medical genetics when many new reference texts were published to help physicians to identify and understand genetic disorders. The most famous of these was Victor McCusick's Mendelian Inheritance in Man. McCusick, as you may know, was a cardiologist turned medical geneticist who worked to catalog all known genetic disorders along with a bevy of fellows and graduate students. And he did so quite successfully over the course of 20 years. This is all of the issues of this catalog. You see that it grew significantly over this time. Eventually they just put it online because it got too big to bother to print. For each catalog disorder, McCusick described the bodily features and provided a diagnostic history with relevant citations. MIM, as it was called, promoted the idea that all disorders had a genetic basis. And here in an early entry for mental deficiency from the early 1970s, what you'll see is that he actually highlights LUBS's finding, which I began by talking about, of the significance of a marker X chromosome associated with mental deficiency. A clear genetic link. Now, a shortcoming of MIM was that in order to actually look up a disorder, you had to have a name for it. Thus, this text could not help clinicians to actually diagnose patients. Mindful of this, in 1970, the pediatrician David Smith published his own reference text, a guide to clinical diagnosis called Recognizable Patterns of Human Malformation. Now, a few years earlier, Smith had coined the term dysmorphology, an approach to studying bodily malformation, which focused on more subtle features than did teratology, which comes from the Greek for the study of monsters. With the understanding that specific clinical patterns likely had discrete genetic causes, dysmorphology, therefore, was teratology redesigned for an emerging genetic era of new and subtly distinct disorders. So, in recognizable pattern, Smith organized disorders by their primary defect, including malformations and bodily growth or the face or the head or the hands, and for each he offered a description, as you can see here, as well as, most importantly, pictures of affected patients. A third set of texts central to the organization of medical genetics were developed by Robert Gorlin, who was actually a dentist, and he sought to help physicians in identifying patterns of bodily malformation as well, especially syndromes involving the head and neck, which he was particularly familiar with. Now, used together as these textbooks often were in the clinic, these texts developed by McCusick and Smith and Gorlin aided clinicians in identifying disorders that were rarely seen, that were, in a sense, rare birds that had a rate, well, they didn't know how frequent they were, but they might be one in 10,000, one in 20,000, and they made the argument that even though they were individually rare, taken together, they actually were a significant portion of human disease and, thus, something worth paying attention to. So in 1981, the physician John Ace described the skill set of dysmorphologist as being similar to that of detectives in his paper, The Dysmorphology Detective. He noted that each arrives on the scene after a main causative event has taken place, whether it be a robbery or the birth of a child with a condition, looks for evidence and then attempts to piece together the remaining clues into a coherent story. He said, quote, well, many of the techniques used by Sherlock Holmes have applications in dysmorphology, perhaps the most striking and immediately useful is the ability to observe small variations from affected, excuse me, expected patterns. Now, next I want to explore how these dysmorphology detectives work to identify new genetic forms of mental retardation. So in the late 1960s, Julian Turner, an Australian pediatrician, was working with boys with an excellent form of mental retardation. She was influenced by Smith and Gorland's textbooks and began surveying her patients in search of common malformation patterns which suggested specific disorders. What she found, however, surprised her. Now, while most patients with mental retardation showed distinct malformations of the face or the head or the hands, she identified one notable subset of boys with an excellent form that did not have any features that she could notice beyond mental retardation. And she later said, quote, we gradually woke up to the fact that to be normal looking in a moderately mentally retarded population was actually relatively abnormal. So this was a notable feature of this group is that they were normal looking and she provided a number of pictures of those patients. Now, at this time, a clinical team in Brazil reported on a similar form of excellent mental retardation in which males looked largely normal except for the presence of one feature, unusually large testes or macro orchidism. Now, this is a bodily feature that could be easily overlooked in the clinic. It doesn't usually appear until after adolescence. They don't often look at their patients completely naked. And actually, until the mid-1960s, there was no sort of standard way of measuring testicles. There was no sense of what an average testicle size was until Andrea Prater developed the orchidometer. And so this feature was mostly overlooked. So following this report from Brazil, Turner began looking for and identified multiple sets of brothers with excellent mental retardation who also showed just one other notable physical characteristic, unusually large testes, and she wrote about them in multiple papers. Based on her own dysmorphology detective work, Turner came to believe that this subtle pattern involving mental retardation and macro orchidism must have a distinct genetic cause. Importantly, this putatively genetic pattern soon made its way into the very medical genetics reference text that I have highlighted. In 1978, McCusick identified mental deficiency with large testes, as you can see here at the top, within Mendelian inheritance in man. And David Smith added Julian Turner type X-linked mental deficiency syndrome in 1982 to his textbook malformation, or recognizable patterns of human malformation. Now it was also at this time that the chromosomal marker identified by LUBS, which I began my talk describing, was once again identified in a family with X-linked mental retardation. The fragile X site, as it came to be called, because the chromosome actually often broke at that marker site, those satellites. The fragile X site came to be another prominent feature in this pattern of malformation involving mental retardation and macro orchidism. Now you may be asking yourself, why had LUBS's fragile X chromosome simply disappeared for so many years between 1969 and you can't see it there, but 1976? There were seven years in which researchers were actively looking for other patients with this specific mutation, but they didn't find them. The answer turned out to reflect changing methods of culturing human cells for karyotype analysis. In 1977, the Australian cytogenesis grant Sutherland showed that the disappearance of fragile X sites was due to a change, earlier in the decade, in the cell culture medium that most medical genesis, most clinical cytogenesis used. Specifically, the addition of folic acid to improve the growth of cells had masked the appearance of fragile sites. So you had to take out the folic acid again in order to start seeing the fragile sites. Now, with this knowledge, physicians and genesis began to study the role of fragile sites in causing mental retardation. Two visual markers, large testes and the fragile X, were used to make a distinct form of mental retardation genetic. During the 1980s, this condition came to be known as fragile X syndrome. In the next section, I want to look at how medical genesis sought to use this association to go about preventing this form of mental retardation, just as Lubbs had suggested. So in 1982, the McGill medical genesis Charles Scriver, reflecting Lubbs' 1969 prediction, pointed to the potential use of fragile sites for detecting and preventing the incidence of mental retardation. He said, quote, an appropriate advance in technology might even permit screening of midterm pregnancies for X-linked fragile sites, like the one shown here. This would be another development with considerable practical and social consequences for disease prevention. So you have a combination of a cytogenic marker, which is now associated with this infrastructure, as I call it, of diagnosis and prevention as a potential public health approach to preventing some forms of, or one form of mental retardation. Now, new genetic approaches for diagnosis and prevention were a common topic of discussion among medical genesis in this period, the 70s and 80s. In 1977, Lubbs, writing with Felix De La Cruz here at the NIH, wrote, we are living in an age of prevention, a period in which the mere treatment or amelioration of a disease or a social problem, although important, is considered a secondary thrust of our efforts. Similarly, the medical geneticist George Frazier put it in 1972, it may be expected that prevention rather than treatment of genetically determined disease will become increasingly important. And in a presidential address in 1986, Arno Matulski, the great medical genesis, said, within the context of the options of today, we must emphasize the importance of prevention. Once a fetal disease is diagnosed, many parents will choose abortion of the affected fetus. Now, medical genesis during this period also highlighted the potential for gene therapy, in order to treat rather than prevent genetic disease. Pointing to the promise of replacing mutant genes with normal copies, Victor McCusick successfully lobbied for extensive government investment in gene and disease mapping, and one of the major outcomes was his morbid anatomy diagrams. He presented these diagrams as, in a sense, roadmaps towards the future promise of gene therapy. While this remained on the distant horizon, however, more immediately these maps represented the growing capability for prenatal diagnosis and the prevention of genetic disorders through abortion. Over the coming decades, this infrastructure for genetic diagnosis notably expanded quite significantly. And just looking at chromosome 15 here, over about eight years from 83 to 91, you can see that the number of conditions mapped to chromosome 15 increased quite significantly. So the morbid anatomy was growing the infrastructure for diagnosis as well as prevention was growing. Now, this growing focus in genetic medicine on prenatal prevention certainly concerns some social commentators and some physicians. Jerome Lejeune, who was famous for identifying the link between Down syndrome and Trizomy 21, lamented that his finding was primarily being used for the prevention of Down syndrome rather than doing the work necessary to try and identify new treatments for various forms of mental retardation. And he actually suggested in 1982 that perhaps this this pholic acid thing, the fact that pholic acid makes in cell culture fragile sites disappear might actually mean that it's a good therapeutic option for preventing fragile X syndrome or perhaps treating fragile X syndrome. And he tried this out and in a very small cohort he seemed to get good results. However, when other researchers expanded the cohort they found that the results weren't there, that it was a bias on the part of the researcher. Other social commentators argued that prenatal diagnosis and prevention gave parents the message that they were responsible for producing the perfect child. And that if they did not, both treatment and support would be lacking. As the bioethicist and physician Mark LePay put it quite early on in this history, quote, there will inevitably be those who armed with cost-benefit analysis demonstrate that it is always easier and cheaper to terminate a genetic illness rather than to treat a child. Now, I think LePay's statement really reflects the emerging free market culture of competitive reproduction. Parents in a sense were given options to ensure having healthy children and if they turned them down they in a sense risked being left behind. Historians have of course debated over the extent to which most war efforts to facilitate genetic disease prevention resemble the compulsory eugenic programs of previous decades. I would argue that while parents in the late 20th century were certainly given choices, they were also provided with a clear sense of what both medicine and society considered to be the right choices and the wrong choices, the right decisions and the wrong decisions. Though that is changing I think in recent decades or at least the last decade. So from here then I want to turn to some new perspectives on mental retardation within society and medicine during the late 20th century. Throughout much of the 20th century, mental retardation was viewed as a medical problem in need of a clinical intervention. The primary means of managing mental retardation into the 1970s was institutionalization. At this time mental retardation was primarily conceptualized within a medical model of disability, which treated it as an undesirable pathology which was innate to individual bodies and thus in need of treatment and prevention. Seeking to gain the support and influence in the 1950s, parents of children with mental retardation formed various organizations including the National Association for Retarded Children. These parents sought educational and social resources and argued that they should be accepted as average middle class Americans despite having a child with mental retardation. They reached out via newspaper articles and postage stamps, advertisements and had the support even of President Kennedy who was a major figure in bringing these issues to light in the early 1960s. They were making the argument that with more research, more support, more medical support, more clinics, more services, they could be accepted into society and their children could be accepted into average white middle class society. The issues of class and race somewhat aside in this, they wanted to be part of their suburban society and their schools and their Boy Scouts and Girl Scouts and other things like that primarily. Now the NARC was suspicious of physicians and challenged the idea that institutionalization was the best way to manage mental retardation as was commonly held in the sort of immediate post-war period. Beginning in the 1970s, the NARC drew on civil rights narratives to promote alternative social models of disability which understood mental retardation and other disabilities as resulting from social choices and assumptions about how people should behave and how they should interact with their environments. Social models of disability argued for greater inclusion and acceptance rather than isolation and prevention. In the early 1970s, NARC advocacy helped to legally establish the responsibility of U.S. states to educate all children with mental retardation. In 1990, the passage of the Americans with Disabilities Act was viewed by the advocacy community as a sign of increasing government acceptance of alternative social models. Intellectual disability also became more visible in popular culture as seen in the network TV show Life Goes On which aired in the late 80s and early 90s starring Chris Burke, an actor with Down syndrome. Americans with Disabilities were increasingly treated in popular culture as unique and valued members of society. Now, the medical community was undoubtedly influenced by the rise of more positive perspectives on disability. While historians have done much to describe the evolving views of disability in government and society, less has been done to examine how new narratives of disability entered the medical community during this period. Late 20th century disability scholars have primarily focused on highlighting the differences between social and medical models of disability. Recently, however, historians and sociologists have sought to identify instances of on-the-ground collaboration across this theoretical divide. Next, I want to present a few anecdotes that I think offer some insight into the evolving perspectives of mental retardation in the medical community. I'm going to kind of book on this in the 1980s and the 2010s to give you a sense of raising awareness within the medical community. I'll actually start by going back just a little bit further. In the early 1960s, the British pediatrician Harry Angelman saw three children with distinct features in common. They had jerky movements, long bouts of laughter and severe mental retardation. Later that year, while on vacation in Italy, Angelman was struck by a 16th century painting, Boy with a Puppet by Giovanni Corotto. And he later said, quote, the boy's laughing face and the fact that my patients experienced jerky movements gave me the idea of writing an article about three children with the title of Puppet Children. Angelman's 1965 report on three Puppet Children turned out to be quite influential. A number of additional accounts of Puppet Children appeared in the medical literature in the coming years. In 1967, his British colleagues suggested the name Happy Puppet Syndrome for the disorder because of the smiling faces of these children and their long bouts of laughter. Now, while the vivid name certainly improved the likelihood of diagnosis and you had diagnoses happening all over the world based in part on these reports and the nature, the descriptive nature of the name, some physicians immediately and soon thereafter took issue with the term. In 1981, pediatricians in Toronto questioned whether these patients were actually as happy as their laughter and their smiling faces suggested. And they recommended, in their paper, quote, on the whole we prefer a less imaginative, eponymous designation. In this case, Angelman's Syndrome in keeping with many precedents of medical usage. Though, somewhat ironically, really, the use of epitomes was on its way out by the 1980s as opposed to being standard, but they saw it as such. The next year, Florida pediatricians Charles Williams and Jaime Frias also argued for a name change to Angelman's Syndrome. Williams later noted that the decision reflected broader moves in medicine, in particular, pediatrics at this time to show greater consideration and awareness for affected families. And he told me, quote, when we were, when we first, when we wrote our first report in 1982, it was a time when there was some awareness about medical terminology and being more concerned about not defending families. We thought happy puppet syndrome was pejorative and not appropriate to use anymore. Now, though concern for families was, by this time on the radar, for some pediatricians in the early 1980s, it wasn't the only reason for seeking a name change. While Williams and Frias pointed to the importance of stigmatization and advocating for Angelman's Syndrome, the Toronto group that I highlighted primarily opposed happy puppet syndrome for reasons of accuracy, rather than its stigmatizing connotation. So a little bit of each. A member of that Toronto group, Donna McGregor, noted to me that many hospital-based pediatricians at this time remained actually quite unaware of family concerns, and this was because they had very limited interaction with parents who were only allowed to visit maybe once a week for a few hours at which time the pediatricians were generally not around. So from here, I want to sort of take the story up to the present and jump ahead to a more recent example of a move away from a stigmatizing term that I think reflects some of the increasing collaboration between parents and physicians in characterizing intellectual disability. So in 2006, the physician and geneticist David Coulin described a new condition initially called 17Q21.31 micro-deletion syndrome, which involved intellectual disability, distinct facial features, and poor muscle development. The name notably placed it squarely within the infrastructure for genetic diagnosis and prevention that I've described here on chromosome 17. In 2012, Coulin noticed that the disorder had been listed online as mental retardation autosomal dominant 17. This was in the online Mendelian inheritance in Man, Omen. Concerned with how families would feel about the use of mental retardation in the name, Coulin brought his findings to advocates on their Facebook page, chromosome 17 disorders. And Coulin essentially asked the parents for input about potentially asking for a name change. And so here he kind of describes the history of the condition and says, this is the OMIM entry, mental retardation autosomal dominant 17. What do you think about this name? Maybe we should think about changing it. And the parents immediately responded. And they said things like, I'd hate to see the term mental retardation as a name. I think that this name has more negativity than it needs to. The R word carries such social negativity. Please, nothing with mental retardation in the name. I don't like mental retardation as a term. So a very clear response from the parents. And one suggested somewhat funnily that he thought that it should be called Coulin Kid Syndrome. Trying to make a play on Coulin's name. An eponymous play in a sense. And this sort of construct of cool kids was actually adopted by the advocacy organizations who, when they introduced their children with their unique features, they said meet the cool kids or they formed a cool kid alliance among other things. So this was picked up by the advocacy groups as part of this conversation. Now, following the response from affected parents, Bert DeVries, the head of Coulin's research group, contacted the online Mendelian Inherents in Man to voice the family's disapproval for this name. And weeks later, OMIM, with the permission from the researchers and support from families, adopted an eponym, Coulin DeVries Syndrome. Now, later, follow-up posts thanked Coulin for his contributions to the diagnosis and naming. So here we have the new entry, Coulin DeVries Syndrome. Mental retardation has completely gone from the entry, the parents say, Coulin Syndrome, well-named. Thanks, Dr. Coulin, for your discovery and your name and for asking our input. Thank you, Dr. Coulin, for keeping us informed and changing the name. Very much appreciated. So beyond a medical diagnosis and better understanding of their child's condition, Coulin had offered families something of great value, a non-stigmatizing and legitimate-sounding name. While Coulin was still working very much within a medical model of intellectual disability, his efforts to engage and collaborate directly with families had increased significantly since the earlier story in the 1980s. Now, as I mentioned, my second book project looks at additional instances of new, more inclusive, more positive narratives of intellectual disability as they entered and influenced the medical community during the late 20th century. In particular, I'm going to explore the role of clinical psychologists, genetic counselors, and pediatricians in introducing and promoting these new social perspectives on disability to medical professionals. I want to see how they brought in these ideas, how they were accepted, how they were rejected, et cetera. And that is the next project as I move forward. My last section today, though, I want to focus on the other aspect of this story. So, having given you an example of how the medical community began to change its perceptions of disability after 1980, I want to next turn to a countervailing trend from this era. After 2000, new whole genome analysis technology coupled with the ever-expanding chromosomal infrastructure for diagnosis promised to enhance the power of prenatal diagnosis to prevent intellectual disability. And so our chromosomal infrastructure from 83 to 91 in the Morbid Anatomy Diagrams eventually goes completely online in the form of various genome browsers, perhaps most famously the University of California, the Santa Cruz genome browser. You'll note the similarities here. The banded chromosomal ideogram is still central to the geography of this. It's still central to the construct of what the genome is and how we find genes and disorders within it. Even though it is, of course, much more densely populated with these features. So in the early 21st century, as you, I'm sure, well know, microarray, DNA microarray, brought chromosomal analysis to the molecular level. Rather than visualize chromosomes directly, geneticists used microarrays containing DNA fragments from across the genome. So using those pieces of chromosomes, putting them on a DNA chip, comparing control DNA to test DNA, looking for deletions and duplications or its differences in SNPs, using the power of computer analysis. Now, DNA microarray, of course, could detect tiny deletions or duplications of genetic material, which was useful when patients with putatively genetic conditions had chromosomes that appeared normal under the microscope. So your chromosomes might look normal. We can't see anything missing or extra. The microarray, though, very clearly identifies a 1P36 deletion as seen here, which is associated with a particular form of intellectual disability. Now, in many instances, these genetic variations, like that one, were found that were of unknown clinical significance. Nobody knew what it meant to have a deletion or a duplication there. Whether these findings were benign variants or disease-causing mutations was a question that geneticists primarily left to be determined based on the collection of additional cases and variants over the coming years. But things got complicated in 2005 when the obstetrician, Arthur Baudette, at the Baylor College of Medicine, began using these techniques, microarray, prenatally. Genetic variants of unknown clinical significance were detected in 12 of his first 98 cases. 12%, 13%. The findings left parents with a difficult decision. They had to choose whether to abort a potentially abnormal pregnancy or potentially a normal one. This was unknown. And there was no time to do more research and find out because the pregnancy was ongoing. Now, Baudette's group, of course, acknowledged the potential for anxiety-inducing results from prenatal microarray, but expressed confidence in their protocols to manage this uncertainty. And this included testing the parents' DNA, doing the same analysis to see if that variant was inherited from one of the parents, in which case they would assume it was benign, though it wasn't always necessarily benign. And by looking at various databases of genomic variants to see, has this been found before and what does this mean? And these databases are continuously growing. Even with these management protocols, however, providers acknowledged the likelihood for increased anxiety. The obstetrician Eugene Pergament said, quote, the improved detection rate may be more than offset by the anticipated exponential increase in uninterpretable results concurrent with the anticipated increase in parental anxiety. Baudette and his supporters of prenatal microarray instead chose to focus on the future promises of new knowledge. In 2012, they said, quote, efforts should continue to focus on reducing the likelihood of results of uncertain significance by continuing to contribute to variant databases to expand our knowledge of the variation of the human genome. Another similar supportive group said, as additional experience with microarray analysis is obtained, uncertain results should become much less frequent as many of these findings will be able to be reclassified as either benign or pathogenic. They will be neatly put into one box or the other. Going perhaps even further, Dutch obstetricians encouraged more prenatal microarray to discover new variants. They said in 2014, quote, to allow the discovery of new pathogenic variants, whole genome array platforms should be recommended in the prenatal setting. Now, as I'm sure you know, increasingly a commercial market has developed for prenatal microarray, in which companies like Combi Matrix promise both physicians and parents the whole picture. Prenatal microarray has been presented as a technology that will overcome previous uncertainty and the risk of a missed diagnosis. This testing can detect mutations associated with intellectual disability and give parents the choice of prevention. And this is one of their ads from 2010, which I picked up at a genetic counseling event. The puzzle piece with the chip on the pregnant belly tells you everything you need to know. And the advertisement is get the whole picture. Now, some commentators have pushed back on all of this, criticizing the research focus of microarray providers in a more laboratory setting. So, bioethicists also in the Netherlands responded, quote, prenatal microarrays are a research tool rather than an instrument of clinical care. Professionals who want to offer undirected arrays to their patients should make it clear that the main purpose of doing so is research. And this can certainly be said of the microarray companies as well. Others have highlighted the impossibility of guaranteeing a perfect baby and warned about the implications of parents thinking that they can get this or going after one. So, the bioethicists Evelyn Schuster said in 2007 as this was just being rolled out, quote, these technologies prompt constant revisions of our view of health and upward redefinitions of normality that will probably cause more rather than fewer abortions of healthy babies. In short, the quest for a healthy baby could cause parents to have no baby at all. So, indeed, not all prenatal diagnostic providers and commentators saw a positive value in more. Some argue that diagnostic providers were overlooking their current patient's best interests in order to produce more genetic variants to examine and potentially improve diagnosis in the future down the line. Now, that said, many prenatal diagnostic providers presented the expanding scope of testing as a win-win situation for parents, clinicians, and researchers. More genetic information met more knowledge and more choice for women, while promising to improve the reach and accuracy of prenatal testing to identify with greater certainty the putative genetic warning signs for disability in the prenatal context, and hence the countervailing trend of increasing the ability to reduce intellectual disability to a genetic finding, to a copy number variant, and prevent it prenatally. So, let me just wrap up briefly with some conclusions. So, today I have presented various aspects of my ongoing research program, which looks at evolving medical and social approaches to characterizing and managing intellectual disability as a genetic condition. In doing so, I highlighted the countervailing trends that shaped this period, once more social support and acceptance, as well as ever-increasing options for genetic reduction and prevention. What can a historian of medicine add to this story? Well, I think historical analysis can help to bridge the ideological divides between the social and the medical models of disability, which have significant political and theoretical meaning, but I think do little for most people with disabilities in their everyday life. A historical examination of how divisive social and medical perspectives on disability have both softened and hybridized over the years will offer insights for how gaps in the understanding and the trust between clinical professionals and disability communities can be bridged in the future to hopefully improve the care of both people and families affected by intellectual disability. Thank you very much. Thank you. So, I wouldn't want to suggest that there's been absolutely no advances in this area based on our genetic research. There have been some, but the promise was much, much greater, I think, than the current outcomes in terms of treatment. Gene therapy was the great promise and sometime in the 1990s into the 2000s realized that wasn't really working out very well. In the 2010s, there have been some efforts and some successes in gene therapy, so it's not completely lost. What I would say is that perhaps one of the best things that can happen is not necessarily purely focused on medical treatment, so I think we'll continue doing that, but also new social ways of thinking as we have of intellectual disability as a form of variation as opposed to a form of pathology. The more we can do to normalize and integrate individuals affected by these conditions, and to do less to pathologize their current variability, the more we can actually do to treat them without treating them in a directly medical sense. So, there are... disability is a very broad category and it's a difficult one to work with. It's a contested category as well. Many deaf people in deaf community wouldn't consider themselves to be members of a disability community more broadly. Some disabilities, we have a pretty good sense of being genetic, some forms of deafness are, some forms are not. I would argue for a sort of... whether genetic or not a broader sort of move, and I think we've done this in terms of physical disabilities in particular and in terms of others, towards sort of building a world, building a space that is more accessible, that flattens out the challenges, the barriers that we... without really consciously thinking about it, pose for individuals with disabilities. But there's real challenges here and genetics can play both ways. Parents who are deaf can try to have a child that is deaf and these are ethical issues that I like to discuss with my students and they're difficult ones and so genetics can be used in multiple different directions. We still struggle with medicine with that and it's not the predominant mode of medical care that has so much potential in each other again. I think it's interesting that we're moving from abortion as one opportunity and thinking about gene editing as well in a realistic sense of the case. I was going to mention that there's a historical, again yesterday, the Social Security Administration registered ruling of the Federal Register about how genetic tests are used to disability determination and so that's kind of an interesting work. And just to note, as a clinical geneticist, the title of Smith's book is never used by us, we just call it Smith's. That's how important it is in the field of genetic editing. So I'll stop there. Thank you very much. So any... Yeah, I just had one thought. So as you look through this, I mean it sounds like, and you didn't really touch upon this, but the issues of class and race as this plays into this, because I think there's a question of access and so can you give some sort of insight into sort of how the, even though genomics has become more accessible in some ways, it's become in some regards less accessible to certain communities and so how does that play into this whole idea of individuals who suffer from intellectual disability and this sort of leveling the playing field for everybody to have these sort of choices? Great. Yeah, so importantly disability identities and disability advocacy intersects with, you know, racing class identities and even going back to the 1950s, I tried to highlight how the NIRC was primarily a group of white middle class parents who actually wanted maybe not actively but passively to isolate themselves from minority and lower class communities because they didn't want the taint of eugenics, which they really still felt very, very really in the 1950s. I think what I've noticed in recent years is that initially when prenatal diagnosis came online in the 70s and the 80s, it was primarily something which was pursued by women who were particularly knowledgeable. They knew it was out there. They had the means both educationally and financially to go after it and that interestingly enough in recent years and this doesn't apply across the board that there's still a lot of sort of exclusion from medical care and pregnancy but in recent years it seemed to me like it's the people who are most educated and most sort of aware who are actually able to exempt themselves from prenatal diagnosis. That prenatal diagnosis increasingly with non-invasive techniques with blood draws which are doing a lot more than I think women really appreciate is becoming so standard that it's only the people who are savvy enough and knowledgeable enough to avoid it who are able to avoid it. Now that said, I'm sure that there's still a lot of problems with access based on racing class lines and I certainly am supportive of I would say that even the most stringent disability activists would say that everybody should have access to prenatal healthcare and even perhaps genetic testing but that they also need to have access to social more positive and inclusive perceptions of what it means to have a child with Down syndrome. It's not that you shouldn't have the choice and have the test but you should have also an alternative perspective on what this diagnosis means and that could also be missing. In birth defects and intellectual disabilities what was some and not with all of them and the people who trained the it was sort of incidental whether it involved so why did you pick that frame so certainly, you know, Victor Minkusic's book wasn't contained in disorders of intellectual disability nor is this primarily birth defects. Right. So what I essentially part of it was the chance of the conditions that I chose as my case studies Fragilex syndrome, Prader-Willi syndrome, Angelman syndrome, and 22Q11 initially DeGeorge syndrome which are all associated with intellectual disability but what it got me thinking about was okay, when I look at a medical text from before 1950 the primary way in which, and I showed it up here, that intellectual disability is talked about is in terms of level of severity and we still talk about that we still measure IQ we still talk about mild, moderate, or severe but it's always linked also to the dysmorphology to the birth defects as well that looking for a genetic cause means that you can't just look at intellectual disability you also have to look at the other features that you can in a sense isolate it and so that's part of the reason that I that I grouped it that way is that in many ways a history of eugenics broadly construed if you will is a history of how our society has managed this issue of variability and intellect or mental retardation as it's been previously called and so I sought to sort of tie it together by looking at that theme over time and I saw birth defects as a broad category intersecting with intellectual disability at the point at which dysmorphology becomes an issue that mental retardation becomes one becomes part of a broader pattern of human malformation in a sense even if it isn't a physical malformation if you look in Smith you will probably see for a lot of those conditions mental retardation I was glad you mentioned the prenatal diagnosis now is being discreet like it's just a block block but I think from a historical perspective and the only reason I'm mentioning this is because that's the subject matter that you're dealing with it's only been about 30 years ago that if my memory serves correctly that the risk of fetal loss with prenatal diagnosis was about 1 in 400 to 1 in 500 is that correct that you think back about I would say it was sure, I think it was assumed to be higher than that even higher I underestimated talking about fetal loss probably to the end of the year so that the 1 in 200 1 in 200 and CVS was even more significant so that the discussion in a historical context would have been very different just 30 years ago than what we're having today but the discussion about information then is much easier in other words providing that information in a prenatal fashion the social issues are different and one could be much more important with no risk well, I'm hesitant to say no risk and the reason for that is because these blood draws are one of many prenatal diagnostic approaches which are not even really diagnostic they're screening approaches and CVS and amniocentesis continue to be part of prenatal diagnosis invasive is still important and there is still a sense of risk associated with that and so getting a certain level of testing still involves a certain level of risk to the fetus and the numbers are the numbers but at the end of the day different people interpret risk in different ways and so the difference between 1 in 500 and 1 in 100 to a pregnant woman could be the world of difference or completely immediate loss there's an interesting story out there going back to probably at least the 1990s the assumption that the age 35 for doing amniocentesis for Down syndrome was directly linked it was essentially came out of the amount of risk that the 1 in 300 chance met the 1 in of losing a pregnancy from amniocentesis met the 1 in 300 chance of having a child with Down syndrome at age of 35 and thus 35 is the age the reality though is that 35 was established as the age before the risk for amniocentesis was well established at all and so it came from other factors in which a colleague of mine is currently still exploring it's a complicated story actually where that age comes from but now it just seems obvious that that is the age so I wouldn't say that the risk for amniocentesis has dropped that much over 20 years or something it's more that because of the variations in how we screen that lead to amniocentesis amniocentesis are the things that have decreased the number of individuals who are given an opportunity even with the current amount of basically of testing for screening as you said if you find a positive there the appropriate response is to then go to CVS or amniocentesis although in practice that often do escape yeah amniocentesis is no longer the first step it is a a response to risk that is determined in other ways besides just age or pre-existing genetic risk factors thank you okay so we are over time so are there any other questions or comments that I get everyone? alright thank you very much I know everyone is terribly busy this was I think a wonderful lecture and a very wonderful question thank you again alright thank you thank you all thanks