Probenecid
", medicine 3x a day."
By: Denise H. Rhoney, PharmD, FCCP, FCCM
- Ron and Nancy McFarlane Distinguished Professor and Chair, Division of Practice Advancement and Clinical Education, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina
https://pharmacy.unc.edu/news/directory/drhoney/
Building on Turn Today medicine 6 year course , the presence of iron-sulfur clusters in enzymes bough’s foundation symptoms you need glasses , Joseph Wong purified B symptoms 16 weeks pregnant . The puri fied enzyme was yellow-brown in color and contained catalytic center of aconitase symptoms uti , where it is involved in revers about 3 atoms of iron/subunit. Inactivation by oxygen ible addition of water in the interconversion of isocitrate led to bleaching of the chromophore and loss of iron (44). I recalled from freshman iron-sulfur clusters are found in enzymes in which they chemistry that ferric sulfide is black. Oxidation of the clus are crucial elements in the glutamine amidohydrolase ter leads to extensive loss of native protein structure in active site. In Lerner cloned and sequenced pyrB and showed that adequately nourished cells, oxygen is rapidly consumed at the gene lay within a cluster of pyrimidine biosynthetic the cell membrane, whereas in starving cells, oxygen is genes (61, 62), as had been suggested by genetic mapping able to diffuse into the cell and react with the enzyme’s studies of Potvin et al. It eventually became clear that the pyr pro studied in collaboration with Janet Smith’s and Howard moter was not contained on the segments cloned and Zalkin’s groups at Purdue University. Like a number of characterized by Lerner and that the region specifying it biosynthetic enzymes leading to multiple end products, could not be cloned in E. Two more transcription terminators were found in x-ray crystallography and characterization of mutant front of each of the initial genes of the cluster. Turner also recognized, was tested and refined by extensive genetic and molecular following insights gained from the studies of Charlie biological experimentation. This structure, called the PyrR-binding forming and, as a result, permit a downstream terminator loop, is located in the leading strand of antiterminator hairpin to form. Binding of PyrR is stim terminator regions, were positioned in front of each of the ulated by uridine nucleotides and antagonized by first three genes of the pyr operon. From these observa guanosine nucleotides, which explains how pyr expression tions, Turner et al. PyrR-dependent attenuation of pyr genes is widely modest refinements, has withstood rigorous testing. In some species, PyrR While these studies were in progress, we became aware apparently acts as an inhibitor of translation by binding to that Jan Neuhard’s group in Copenhagen had sequenced a PyrR-binding loop located adjacent to the ribosome the pyr operon from the thermophile Bacillus caldolyticus binding site for a pyr gene. The gene is not part of the however, demonstrated that it encoded a uracil phospho B. Soon, both groups obtained con that pyrG expression is specifically regulated by cytidine in vincing evidence that PyrR is an unusual bifunctional pro Bacillus. Their fresh and to slippage of the transcript on the template and reiterative original ideas led to our most significant findings. They addition of extra G residues to the transcript until a C pushed me to learn powerful new technologies, especially residue is finally inserted and transcription continues. Teaching in the class resulting transcripts with a series of extra G residues are room and informally in the laboratory forced me to able to cause antitermination by base pairing with the deepen my understanding of a broad range of biochemical leading strand of the downstream terminator. My former students tend to give me a lot of elevated synthesis of full-length pyrG message results. Reiterative transcription occurs in cells grown on orations with Janet Smith, Howard Zalkin, Bjarne Hove limiting cytidine and is essential for transcription attenu Jensen, and Michael Becker, but I shared efforts with many ation in vivo. Regulation depends only on the sequence of others in biophysical characterization of our favorite the pyrG initially transcribed region and the properties of enzymes. It has been a particular positive interactions with scientists from many other source of pleasure to me that this remarkable story was counties, including Australia, Canada, France, Great Brit developed in close collaboration with my former student ain, Italy, Spain, and Sweden. The opportunity to live and Chuck Turnbough, with whom I also recently published a do research for extended periods in Freiburg with Helmut thorough and critical review of research on the regulation Holzer, when I was a Guggenheim Fellow, and in Copen of pyrimidine biosynthetic genes in bacteria (68). A theme I have emphasized in these reflections is the great reward and personal pleasure I have received from the Role of Good Fortune doing research with other investigators. As a professor of the reader may have noted how frequently I have biochemistry at a major university, I was, of course, referred in this article to good fortune and to lucky, unex expected to train advanced undergraduate and graduate pected findings. I was privileged to work with many insight as a researcher, candor requires me to admit that I very capable students, several of whom I have named above. I was Most of them have gone on to outstanding independent lucky to spend my entire research career during what must careers in biotech, pharmaceutical, or agricultural science be regarded as the Golden Age of biochemistry, an age companies, in academic research and/or teaching, and in when wonderful discoveries were being made every year medical practice. Several have developed research programs and when powerful new methods of research were being that, to speak frankly, have surpassed my own in productivity developed. Their contributions to science, far possible the cloning and sequencing of genes, facile isola more than my own, constitute my greatest legacy. I was supported by the National 389–402 Science Foundation for both undergraduate research and my 8. Acknowledgments—I am most grateful for the many important contri 262, 4477–4485 butions of my mentors, collaborators, former postdoctoral students, and 39. Hence, this prologue will provide an overview and some guide O posts for the route. Because this concept was heretical at the time and because substantial further work was necessary to cement these concepts, the work moved slowly. From these determinations, there was no doubt that sequences with identical base compositions had very different properties, and further work in my Wisconsin laboratory (described below) during my Assistant and Associate Professorship days verified this conclusion. However, a complication related to this unorthodox interest was that virtually all methodologies for determining structures and their biological functions had to be developed and were not carryovers from other fields (3). Most educators know the old adage that graduate students really do not understand the mag nitude of the problems that they are encountering because, if they did, they would never undertake their thesis project. Interestingly, the neurological and human more doubtful of success, nor more dangerous to manage, genetics communities were quite receptive to the con than the creation of a new system. Polymorphic In the late 1990s and early 2000s, the convergence of My early educational years at Ohio Wesleyan University bioinformatics, human genetics, molecular biology, and (1956–1960) and my Ph. However, when I left his laboratory 24 netropsin binding, circular dichroism, triplex forma months later, the entire code was finished, and he shared tion, viscosity, x-ray diffraction, lac repressor binding the Nobel Prize in 1968 for these discoveries. Third, it was realized tion and to utilize different types of polymerases for their by Bob Blakesley in my lab that single-stranded phage preparation. This Roger Wartell and I (3) stated in 1974, “The observation discovery was confirmed by N. This discovery was followed after a more on target in the interpretation of these experiments; four-year time period by the important findings of P. The Department of Biochemistry and related transcription by the three-stranded structures (8). This departments had extremely high standards with a number work was in concert with the earlier studies of T. Lardy, Bob Burris, Harry Steenbock, Julian Davies, Bill Langridge (9) and the contributions by the group of M. Rich and associates (14) reported the x-ray ior and highly respected faculty member, Harlyn Halvor structure in a single crystal of a hexanucleotide containing son, had approached the administration of the University strictly alternating C and G residues in a left-handed Z of Wisconsin in 1960 to explain the developing area of helix. This research program along with its funding in the new envi extremely competitive and energetic group of faculty cre ronment. Also, my sabbatical experience part because of the environment and in part because of the (1976–1977) with Dr. By this time, I sequences with repeating C and G bases had a left-handed had been broached by at least 25 other institutions to con helix. The faculty are caused by different environmental conditions; was interesting, productive, and adroit at grantsmanship (T-G)n (C-A)n adopts a left-handed structure; plasmids and was working on important research problems. The capacity of if you pick the right institutions and if the mix of research sequences to adopt either cruciforms or left-handed Z programs is beneficial, the results can be fantastic. However, a number of efforts from my lab to the cruciform state were investigated (38). Unfortunately, some geneticists use the term pal sequence, the A runs are regularly spaced with a periodic indromes to refer to the inverted repeat sequences that ity of 10 bp. Of course, we suspected that these properties Cruciforms—The early work on cruciforms was highly were due to the formation of triplexes at the sites. This pair of discoveries was posed by other laboratories, which I felt were likely to be significant because it served as a harbinger for a family of incorrect (43). However, I challenged Jeff Hanvey to intriguing structure but remains to be fully characterized.
Oats may be tolerated by some patients treatment meaning , theoretically permitting consumption of an increased variety of different foods symptoms dizziness nausea . Unfortunately 20 medications that cause memory loss , commercially available oats products are often contaminated with gluten containing grains during growing symptoms pneumonia , transportation and milling processes. However, since most celiac patients that respond to a gluten-free diet absorption will improve so that these minerals and vitamins usually normalize without the need for specific supplements. Growth and development in children also requires monitoring after a gluten-free diet has been initiated. A skilled dietitian is helpful to review the diet initially and to serve as an information source. Patient support groups and online information and other literature may be available, such as, to locate sources of gluten-free products. These gluten free products maybe costly and in some developing countries, they may also be difficult to access. Treatment compliance is important as a gluten-free diet is protective against the development of lymphoma. Treatment of symptomatic disease may improve nutritional parameters, including bone mineral density measurements. Treatment may eventually result in increased body weight, body mass index, fat mass, bone mass, triceps skin fold thickness, and nutritional as well as biochemical status, including iron absorption parameters. The patient and their family must be educated in the disease, and accept the need to be on a gluten free diet for life. Persons with gastrointestinal symptoms may choose to place themselves on a gluten-free diet, prior to proper investigation and establishment of the diagnosis. Shaffer 255 unrelated to those at the time of diagnosis such as symptoms of gastroesophageal reflux disease, abdominal pain or constipation (Carroccio et al. A high throughput, immune-based assay using monoclonal antibodies specific for immunotoxic peptides has facilitated their detection in food (Moron et al. It should be noted though that histological changes improve initially in the more distal small bowel, so repeated biopsies from proximal duodenum may show little initial improvement (Jadrosin et al. The proposed new Codex Alimentarius Standard for naturally gluten-free foods is a maximum of 20 ppm. Gliadin may be neutralized by complexing it with a polymeric binder, and thereby preventing the toxic effects of gliadin on the intestine (Pinier et al. Combinations of bacterial and fungal proteases when fermented with gluten may decrease gluten concentration by more than 98%. A reliable extraction protocol has been developed to remove immune responsive gluten proteins in wheat, rye and barley (van den Broeck et al. It is likely caused by a multifactorial complex interplay among genetic, environmental, microbial, and immune factors in a genetically predisposed host (Mizoguchi and Mizoguchi 2008; Podolsky 2002), with uncontrolled inflammation affecting the mucosa as well as other layers of small intestine and/or colon (Fretland et al. There may be a mild or a disabling clinical course with unpredictable relapses, perianal and extraintestinal complications, as well as frequent medical encounters including hospitalization, unpleasant therapies, and surgery. These all contribute to the sufferer’s sense of hopelessness, depression, anxiety, sexual disturbances, unemployment, disability or need for sick leave from this debilitating disease (Caprilli et al. Among first-degree relatives, siblings (most often, female siblings) are most often affected with Crohn disease, compared to parents or children (Freeman, 2002). The markedly increased concordance rates in identical twins can only be explained by an underlying genetic component. With the completion of the human genome sequence, it became possible to perform ‘genome-wide association studies’, providing systematic assessment of the contribution of common variation to disease pathogenesis. This approach has had an unprecedented impact on our knowledge of the genetics of many autoimmune diseases. The product of this gene is expressed in many cells, including monocytes, dendritic cells, Paneth cells and intestinal epithelial cells. Further understanding of regulatory elements within non-coding genomic regions and gene–gene interactions will lead to a better understanding of the underlying mechanisms that cause disease (Xavier 2007). Difficile infection o Upper respiratory tract and enteric infections o Psychological Stress o Pollution, diet Adapted from Ardizzone and Bianchi Porro 2005 fi Immune Function the innate immune system is the first line of defense against resident luminal microflora and invading pathogens, and can respond to a wide variety of microorganisms. The innate immune system has evolved to monitor the resident microflora and relay danger signals in response to infection by invasive organisms. These pathways in turn lead to the activation of transcriptional programs resulting in the broad-spectrum non-specific killing mechanisms of innate immunity. These mechanisms include synthesis of reactive oxygen species, activation of the complement protein system, secretion of chemokine and cytokines for chemotaxis of phagocytotic macrophages, and secretion of antimicrobial proteins by Paneth cells (Goyette 2007). Paneth cells are specialized epithelial cells located at the base of small intestinal crypts, which monitor the intestinal lumen and are considered important mediators of mucosal innate immune defense. They contribute to host defense and maintenance of the gastrointestinal barrier through the luminal secretion of a number First Principles of Gastroenterology and Hepatology A. Shaffer 263 of antibacterial peptides (defensins, lysozyme and secretory phospholipase A2), which protect nearby intestinal stem cells and control microbial density. The intestinal lamina propria contains a complex population of immune cells that balance the requirement for immune tolerance to the normal luminal microbiota, but also with the need to defend against pathogens, the excessive entry of luminal microbiota, or both (Abraham 2009). The hallmark of active inflammatory bowel disease is a pronounced infiltration into the lamina propria of innate immune cells (neutrophils, macrophages, dendritic cells, and natural killer T cells), as well as adaptive immune cells (B cells and T cells). Interleukin-23, secreted by macrophages and dendritic cells, may contribute to Th17 proliferation, survival, or both (McGeachy and Cua 2008). Levels of interleukin-23 and Th17 cytokines are elevated in the colonic mucosa in both Crohn disease and ulcerative colitis (Abraham 2009). The defective T-cell mediated regulation is associated with a disruptive interaction between the immune system and gut luminal factors. In addition to this ‘naturally occurring’ Tregs, there are also ‘adaptive’ Tregs, the so-called Tr1 and Th3 cells (Huibregtse 2007). Regulatory T cells appear to be key players of immune regulation, and they have important functions in suppressing unwanted inflammatory responses towards self-antigens, and the antigens of endogenous intestinal bacteria. Intestinal B cells produce IgA antibodies, which contribute to immune protection without provoking inflammation. In animal models of colitis, both anti-inflammatory and proinflammatory roles of B cells have been described. In contrast to innate immunity, adaptive immunity generates a slow and more targeted response involving antigen specific recognition and immune memory. In addition, since most of the antigens encountered by the mucosal immune system are derived from food proteins and commensal bacteria, the immune system must remain relatively unresponsive to avoid responses to harmless antigens and maintain epithelial integrity. It has been proposed that tolerance to these luminal antigens, also known as oral tolerance, occurs through a state of active cellular suppression or clonal anergy of immune reactive cells induced by specialized regulatory T cells (Mowat 2004). A common feature of gut inflammation is increased epithelial permeability, both paracellular. However, the inflammatory process itself leads to increased intestinal permeability (Bruewer 2003). There is likely an interaction between the intestinal microbiotics, and genetics, immune function and intestinal permeability. The microbiota then provides a constant stimulus for the host immune system (Shanahan 2004, Tannock 2005). The associated lesions and the immunologic changes indicate a breakdown of mechanisms that maintain oral tolerance to components of the microflora and/or foodstuffs (Canny and McCormick 2008). The findings supporting the presence of an altered immune status include an exaggerated mucosal antibody response against intestinal bacteria. The antibacterial peptides known as “fi-defensins” are produced by Paneth cells at the base of crypts in the terminal ileum (Strober et al. The Vienna classification, and later, the Montreal classification, have both already been applied to Crohn disease populations in Canada but not for ulcerative colitis (Freeman 2001, Freeman, 2007). Shaffer 266 *B1 category should be considered ‘interim’ until a prespecified time has elapsed from the time of diagnosis. The cardinal symptoms include crampy abdominal pain, diarrhea (watery, may be bloody or may show signs of malabsorption), weight loss, fatigue, extraintestinal symptoms. The Montreal Working Party has recommended that the term ‘‘indeterminate colitis’’ should be reserved only for those cases where colectomy has been performed and pathologists are unable to make a definitive diagnosis of either Crohn disease or ulcerative colitis after full examination (Silverberg 2005). Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management 2006. Blood tests are useful to suggest possible active inflammation, as suggested by anemia, leukocytosis and thrombocytosis. These serological markers may also be useful to predict clinical course and therapeutic response. A stool calprotectin greater than 10mg/L predicts organic disease, with a sensitivity of 89% and a specificity of 79% (Palmon 2008).
. Quotes & Sayings.
This was done by Hartwell treatment 5th finger fracture , McLaughlin medicine 7 , and Warner 1990 symptoms 9f anxiety , we noticed a paper just published by Janice Kranz (37) in conjunction with the celebrated screen for cdc and Connie Holm medicine abuse , who described a general method to mutants. The ade2 mutation causes accumula degraded in the absence of simultaneous production of tion of an intermediate that is converted to a red pigment. Thus, the yeast gene homologous to X could around that time that led to our success in devising a easily be isolated and identified by screening plasmid method of mutant isolation. We realized that if we devised an artificial system on a plasmid that could functionally complement mutations in essential components in the Pol I machinery, the Kranz and Holm method could be used for our purpose. The remaining seven encoded proteins had not lated several mutants, each carrying a ts mutation in the been known previously. Therefore, the identification and work and immediately constructed the plasmid shown in purification of these factors would have been very difficult Fig. The difficulty of mutating sequences of all tandemly with our genetic approaches related to E. When I found that we were able to isolate rrn mutants in Legacy of the Early-day Molecular Biology early 1991, I decided to phase out the E. The other was the informational school initi in 1994 (49, 50), formally ending our research using pro ated by people asking questions regarding the nature of karyotic organisms. Gunter Stent’s proclamation of the end of 1960s, some of the people interested in solving genetic progress in Molecular Biology in 1968 (1, 2) was made as a problems tried to use biochemical approaches without molecular biologist of the informational school. There was a popular interesting to note that even regarding information trans expression defining molecular biologists as “people prac fer from genes to protein, several fundamental discoveries ticing biochemistry without license. The for me to have decided to work in Seymour Benzer’s lab general notion of the end of major progress in (prokary oratory from 1959 to 1960, doing research on T4 even otic) molecular biology, as publicized by people like Stent, though it was classical phage genetics. This experience stimulated the exodus of early molecular biologists from helped me to use genetic approaches without a proper the prokaryotic systems in the late 1960s to 1970s and license in my subsequent research career, which covered switching to new areas of research not explored in the both prokaryotic and eukaryotic molecular biology. Features unique to mul this use of genetic approaches in our yeast research was ticellular organisms aside, it became obvious by the mid very satisfying to me. One Of course, the amazing technical progress in the past such person was David Botstein, who described the story decade or so, which led to the successful complete of his switch to yeast in a highly interesting essay (55). One can now analyze cellular activities meeting during a summer in the mid-1970s, almost cer as a whole using genomic, proteomic, and metabolomic tainly a meeting related to ribosome biosynthesis, and approaches, i. They include my postdoctoral-time model organism for the study of eukaryotic cells that may mentors, Sol Spiegelman and Seymour Benzer, and other teachers, col correspond to the position of E. Other notable early-day molecular biologists mentioned, otic molecular biologists included, in addition to regula Jacques Monod, John Kendrew, and Max Perutz, also have passed away. Ira Herskowitz, who was much younger than I, also passed away the nucleus (and subnuclear structures like chromosomes prematurely. X800013200 Raquel Sussman From the University of Pittsburgh, Pittsburgh, Pennsylvania 15260 s I look back, I realize that serendipity has played a major role in my life. As far back as I can remember I was interested in plants and animals, enjoying my Aunt Olga’s farm, where I could observe the reproduction of rabbits and A crossed plants of different colors. When I was a teenager a devastating earthquake in the South killed an aunt and two infant cousins who happened to be at the epicenter just for one night. That unfair tragedy convinced me that life had been created by natural forces, and the way to prove it was by synthesizing a living cell in vitro. I wanted to be a scientist and decided that I would direct my efforts toward that aim. My bad grades in high school on all the subjects that required memory, except biology and math, almost prevented me from being accepted to the Faculty of Chemistry and Pharmacy. During my college years I read everything I could find about the biology of cells and decided that I should first study the simplest of all self-reproducing organisms, namely viruses. To get my degree I had to work on a research problem, and by luck I read a paper that W. I asked the Director of the Department of Viruses at the Instituto Bacteriologico de Chile that was dedicated to growing viruses and producing vaccines if I could work on my thesis there and in return help with the work. At that time, the fact that a self-reproducing entity could be just a molecule was of great philosophical discussion and reassuring to me. In 1946, I applied to the Institute of International Education for a scholarship to continue my studies on the chemical nature of viruses in the United States. Serendipity led me to Washington University in Saint Louis, Missouri where the Bacteriology Department had an instructor, A. Bronfenbren ner, informed me that because of post-war constraints the course had not been scheduled. He suggested that I should take the Medical Bacteriology course instead and perform research with him. The project consisted of purifying bacteriophage to determine its phosphorus content. I was the third student that was assigned to that task because the previous ones had found phosphorus and according to Bronfenbrenner the phage had only protein and the presence of phosphorus indicated contamination. I worked hard to purify the phage through more procedures than nec essary and, of course, I found phosphorus. Then, Hershey took pity on me and decided to give a special course on phage the next semester for the 7 graduate students. I will never forget that course because he used phage as units of infection that could demonstrate the quantitative aspects of biological problems. In 1950 when Hershey moved to the Carnegie Institute in Cold Spring Harbor he became famous for the “phage course” that he continued to give every summer. At the end of the academic year Hershey asked me if I wanted to be his assistant for a project he was just starting. I was delighted and asked permission from the Institute of Interna tional Education to stay longer, which was approved. Sol already had a working hypothesis that this strain had “plasmagenes” that controlled the synthesis of the new enzymes, and he expected me to prove it. The first possibility was that a few cells in the growing population spontaneously mutated to gal, followed by selection. I used the statistical analysis of Luria and Delbruck (6) to determine whether this was the mechanism. My results clearly showed that it was a massive population change requiring the continuous presence of galactose. At that time there were no available techniques to determine whether it was a cytoplasmic or a nuclear phenomenon. For example, when I asked him a question about operon induction, involving three specific interacting pro the results that I was getting in phage crosses he did not teins necessary to start transcription of the gal promoter in respond right away, but the next day he gave me 3 type the nucleus. Later Sol contributed significantly to science, written pages with an analysis of the question. He always in a pioneering way, for example studying viruses described the different results that were possible to get that induce cancer. His ego was com ston, Illinois because Maurice had accepted an appoint pletely detached from the importance of the experiments ment as an instructor and established a laboratory in the that we were doing, namely showing for the first time that biology department at Northwestern University. He chose to study deport me in 3 weeks because I had a student visa and was the cellular slime molds, primitive amoebae that displayed not supposed to work as an assistant. I was forced then to two distinct and separate phases, namely growth and dif leave in February. He established controlled conditions to study Another serendipitous event that year was meeting their development in sufficient number and synchro Maurice Sussman, who was Sol Spiegelman’s graduate nously to be able to identify and study the kinetics and student. He was very intelligent and totally engrossed in logistics of key biochemical events, particularly the syn research, and we became inseparable. In 1948 I came back thesis of new proteins that attend differentiation into fruit to the United States to marry him. I wanted children, and although taking care of them has At that time, performing science with Sol was another always been my first priority, I did not want to quit science unique experience. However, at that time, no labora with not many more years of scientific experience but tory would hire a woman with a child and able to work only talked as an old pro. He always had one problem dominat part-time, so I started work in Maurice’s laboratory for 2 h ing his mind and thought about it 18 h a day. Our coffee breaks every4htotalk about experiments and we income was very low and we could not afford baby-sitters. The problem that he assigned to me Moreover, in those days fathers did not participate in the was Saccharomyces chevalieri’s “long term adaptation” to daily care of the offspring. This strain of yeast required days because she understood my passion for science, and so of contact with galactose before the population became with the last two babies she left the family in Chile and positive, in contrast with other strains of yeast that came to help me for 8 months each trip.
He ease treatment jammed finger , alcoholism medications and mothers milk , criminality treatment dry macular degeneration , and various other sociopa developed a variety of methods in twin research [91] thies symptoms acid reflux . They became convinced that the human species and first elaborated methods to correct for biased ascer should be concerned with encouragement of breeding tainment in recessive inheritance [93]. Most of study units were established in the United States the data in formal genetics (such as linkage, nondis (Eugenics Record Office at Cold Spring Harbor) and junction, mutation rate) as well as the mapping of the United Kingdom. Much of the scientific work pub chromosomes were achieved by study of the fruit fiy, lished by these institutions was of poor quality. Many scientists tried to Particularly, many different kinds of human traits such apply the burgeoning insights of genetics to humans. Most serious geneticists the elaboration of a variety of statistical techniques became disenchanted and privately disassociated them required to deal with biased human data. For various reasons, including period saw the development of the basic principles of those of friendship and collegiality with the eugenicists, population genetics by Haldane, Fisher, and Penrose the scientific geneticists did not register their disagree [69] in England and by Wright in the United States. Thus, the propagandists of eugenics this body of knowledge became the foundation of continued their work with enthusiasm, and the field population genetics and is still used by workers in that acquired a much better reputation among some of the field. Thus, many college courses on troversies in England between the Mendelians, on the eugenics were introduced in the United States. Eugenics sterilization laws were passed in relatives in metric traits can be explained by the com many states in the United States, which made it possi bined action of many individual genes [26]. Motulsky criminality for which no good scientific basis of inher who were concerned about the biological future of man 1 itance existed. Thus, socialists publicized such views in Germany of these laws is epitomized by United States Supreme [34]. In 1931, two years before Hitler’s coming into Court Justice Holmes’ statement that “three genera power, the German Society of Racial Hygiene added tions of imbeciles are enough. However, all efforts in this area Eugenic infiuences also played an important role in soon became identified with the Nazi ideology. Using a variety of arguments the propo themselves with the use of human genetics in the service nents of eugenics claimed to show that Americans of of the Nazi state. Recognized scientists, such as Fischer, northwestern European origin were more useful citi F. Lenz, Rudin, and von Verschuer, accepted Nazi lead zens than those of southern European origin or those ership and Nazi philosophy. Since such differences were claimed to be ganda for the new racial hygiene was not formulated by genetic in origin, immigration from southern and east scientists but by representatives of the Nazi party, men ern European countries and from Asia was sharply such as Fischer and von Verschuer [95] participated in curtailed. While solid work in human genetics eign genetic material to be removed from the German was carried out by a few statistical geneticists, there Volk. A eugenic sterilization law was already passed in was also much eugenic propaganda, including that by 1933 that made forced sterilization obligatory for a vari the distinguished statistician Pearson, the successor to ety of illnesses thought to be genetic in origin [74]. Heredity courts were established to deal with interpreta Kevles [46] has published a wide-ranging and tion of the sterilization law. This law was hailed by some insightful history of eugenics and human genetics in eugenicists in the United States even at the end of the the Anglo-Saxon countries. Sterilization laws for eugenic indications fully researched and exhaustive study of the uses and were also passed in some Scandinavian countries around abuses of eugenic concepts. The exact role of the German human geneticists in the increasing radicalization and excesses of the appli 1. We have no record that any voices were raised by became associated with mystical concepts of race, these men in protest against “mercy killings” of the Nordic superiority, and the fear of degeneration of the mentally retarded and newborn children with severe human race in general and that of the German Volk in congenital defects nor against the mass killings of Jews. Often representatives of this movement tact with Mengele when the mass killings at Auschwitz became associated with a dangerous type of sociopoliti were at their height. They warned the public problem” resulted in the murder of about 6 million Jews against contamination of German “blood” by Jewish in the early 1940s [75]. Most followers of the racial hygiene concept human geneticists favored this type of “solution,” their were nationalistic and opposed the development of an provision of so-called “scientific” evidence for a justifi open society that allows individual freedom and demo cation of Nazi antisemitism helped to create a climate cratic participation. They shared this attitude with a sig in which these mass murders became possible [88]. This episode is one of the most macabre and tragic General eugenic ideas divorced from racism and other chapters in the history of man’s inhumanity to man in nationalist notions were often espoused by intellectuals the name of pseudoscientific nationalism. Yet, despite 1 History of Human Genetics 2323 their racist publications, several such “scientists” 1. This attitude toward genetics is shared by some psychologists and social scientists and even a few geneticists who are concerned about the Eugenics was initiated in the Soviet Union [21,34] in possible future political and social misuse of studies in the 1920s by the establishment of eugenics depart human behavioral genetics that claim to show genetic ments, a eugenic society, and a eugenics journal. Eugenic ideals soon clashed with the official doctrine We do not agree with those who deny any genetic of Marxism-Leninism, however, and these efforts were infiuence on behavior or social traits in humans. Scientists who had However, we also caution against a too ready accep become identified with eugenics left the field to work tance of results from comparison of twins and other with plants and animals. Genetic data and pseudodata may be seri carried out between 1931 and 1936, such as using ously misused by political bodies. However, as biolo hypotonic solutions for spreading of chromosomes, gists and physicians impressed by biological variation analysis of cultured embryonic cells, chromosome under genetic control, we would be surprised if the analysis of human oocytes, and cytogenetic studies of brain did not also show significant variation in struc leukemia and other cancers [3,4]. Such variation is expected to affect published in international journals and later taken up intellect, personality, and behavior, and usually will by American and European scientists some 20 years interact with environmental factors. Would the critical chromosome-related discover which genetic variation contributes to such traits, and ies of the 1950s have been made by Russian scientists especially the biological nature of such variation, will if such work on human genetics had not been termi have to await further studies. The later ascendance of Lysenko [45] stified all work in genetics, including that of human genetics, and no work whatever In the 1940s and 1950s a number of institutions pio was carried out in this field until the early 1960s, after neered in research on epidemiology of genetic diseases. Neel’s depart the reintroduction of human genetics into the Soviet ment in Ann Arbor, Michigan, and A. A textbook Northern Ireland and later in Oxford contributed much of medical genetics was published by Efroimson in to our knowledge on prevalence, modes of inheritance, 1964 [22]. A new institute of medical genetics was heterogeneity, and mutation rates of various hereditary established in 1969 under the directorship of the cyto diseases. Recent years have seen a renaissance in this geneticist Bochkov, who had been trained by the well area, with special attention to analysis of common com known Drosophila geneticist, Timofeeff-Ressovsky plex diseases (see Chap. Motulsky search for rare mutations and structural chromosome humans led the way to generally valid biological rules. The hypothesis that some expressed polymorphisms are the genetic sub strate against which the environment acts to determine 1. This locus appears to be of great importance statistically oriented scientists, now entered the main to understand susceptibility to autoimmune diseases. The genetic code was found to be valid for organisms as far apart as viruses and humans. The nucleotide sequences of the hemoglo bin genes were worked out using techniques developed After cytogenetic techniques became available, they in biochemistry and molecular genetics. Many inborn were applied to detect many types of birth defects and errors of metabolism were shown to originate in various intersex states. A specific type of malignancy, chronic enzyme deficiencies, often caused by a genetic mutation myelogenous leukemia, was shown to be caused by a that changes enzyme structure. Banding tech due to diaphorase deficiency and glycogen storage dis niques developed by Caspersson in 1969 made it pos ease were the first enzyme defects to be demonstrated. Soon, biochemical and cytogenetic techniques were combined in somatic cell genetics. The development of methods to hybridize human with mouse cells by Henry Harris and Watkins Work on hemoglobin and variants of the enzyme glu [40] and Ephrussi and Weiss [25] soon allowed the cose-6-phosphate-dehydrogenase and other enzymes assignment of many genes to specific chromosomes helped to establish the concept of extensive mutational and the construction of a human linkage map. Biochemical individuality explained some the developments in somatic cell genetics led to drug reactions and led to the development of the field the introduction of prenatal diagnosis in the late 1960s, of pharmacogenetics [61, 86, 63, 35]. Marked bio when amniocentesis at the beginning of the second chemical heterogeneity of human enzymes and pro trimester of pregnancy was developed. The uniqueness of humans, tissue cultures of amniotic cells of fetal origin, permit which is apparent by the physiognomic singularity of ting both cytogenetic and biochemical characterization each human being, was shown to apply at the biochem of fetal genotypes, assignment of sex, and the diagnosis ical and immunological level as well. In the early 1980s eral other fields (such as the hemoglobin variants and chorion villus biopsy – a procedure done during the the mechanism of sex determination), studies in first trimester of pregnancy – was introduced, and is 1 History of Human Genetics 2525 being widely used. The discovery that neural tube variants are being used in family or association stud defects are associated with increases in a -fetoprotein ies as genetic markers to detect the presence of of the amniotic fiuid permits intrauterine diagnosis of closely linked genes causing diseases. Ultrasound tion of genetic disease has been achieved by utilizing methods to visualize the placenta and to diagnose fetal nucleotide probes that are homologous to the muta abnormalities added to the diagnostic armamentarium. The polymerase chain this noninvasive method allows phenotypic diagnosis reaction, together with rapidly increasing knowledge of a variety of fetal defects more frequently. Genetic counseling – often by specially trained specific mutation that causes the disease is known.