Dr Lewis Kitchener Dahl, the Dahl Rats, and the “Inconvenient Truth” About the Genetics of Hypertension
2015; Lippincott Williams & Wilkins; Volume: 65; Issue: 5 Linguagem: Inglês
10.1161/hypertensionaha.114.04368
ISSN1524-4563
Autores Tópico(s)Blood Pressure and Hypertension Studies
ResumoHomeHypertensionVol. 65, No. 5Dr Lewis Kitchener Dahl, the Dahl Rats, and the "Inconvenient Truth" About the Genetics of Hypertension Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBDr Lewis Kitchener Dahl, the Dahl Rats, and the "Inconvenient Truth" About the Genetics of Hypertension Bina Joe Bina JoeBina Joe From the Department of Physiology and Pharmacology, Center for Hypertension and Personalized Medicine and Program in Physiological Genomics, University of Toledo College of Medicine and Life Sciences, OH. Originally published2 Feb 2015https://doi.org/10.1161/HYPERTENSIONAHA.114.04368Hypertension. 2015;65:963–969Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2015: Previous Version 1 IntroductionThe year 2014 is a special year for the Dahl lecture because it marks the Centennial birth year of Dr Lewis Dahl (Born on December 11, 1914). Hence, I am especially privileged to be commemorating the occasion with this year's Dahl memorial lecture.It is traditional for memorial lectures to be presented with a note of reverence to the iconic investigators who influenced our thinking in profound ways. Because my entire research career is based on the Dahl rats, which were generated by Dr Lewis Dahl, I was familiar with Dr Dahl's scientific contributions not just through his articles, but through conversations with my mentor, Dr John Paul Rapp, who was technically the scientific successor of Dr Dahl as he inherited the Dahl rats before Dr Dahl's sad demise in 1975. An additional source of brief information preceding the death of Dr Dahl is presented in an article by Dr Brian J. Morris,1 the 2010 Dahl Award honoree. Thus, in preparing for this lecture, it was obvious to me that the scientific community barely knows Dr Dahl as a person. Because learning about the personal history of scientists, especially prominent ones, inspires one to relate and grow likewise; the first part of this lecture article highlights the life and times of Dr Dahl. This will be followed by an update on the work that we have conducted using the Dahl rat as a genetic model of hypertension.My attempt to reintroduce Dr Dahl would not have been possible but for the World Wide Web (Internet), searches through which eventually lead me to the source—the eldest daughter of Dr Dahl, Dr Karen Dahl. The data being presented was collected mainly through personal communication with her a few days before the Dahl Award Lecture was delivered in San Francisco, as well as from a book that she pointed me to, which was written by one of Dr Lewis K. Dahl's brothers, Dr Robert A. Dahl.2Lewis Kitchener Dahl: A Brief BiographyI will consider myself successful if I engage your permanent interest in concepts related to hypertension, which I have been studying exclusively for more than two decades. I will remain unperturbed, however, if you do not accept all the details.3These words of Dr Dahl bring to mind an image of a person of strong conviction. The historical makings of this deep thinker, who contributed enormously to our knowledge on the relationship between salt and hypertension, originated in a family farm called Dahl Vestre, or West Dahl,2 in Trondheim, Norway. It was here that Dr Dahl's grandfather, Ivar Dahl, was born as the youngest of 6 siblings. Seeing no chance of acquiring a farm for himself, he immigrated to America in 1865. Ivar's oldest son, Peter Ivar Dahl, went to medical school, married Vera Lewis, and settled down as a physician in Canton, North Dakota. Driven by a better job prospect, Peter and Vera moved to Balf, in Edmonton, Canada, where, on December 11, 1914, their first son was born. They named him Lewis Kitchener Dahl.The first and last names are obviously from Dr Dahl's mother's maiden name and family name, respectively. The origin of the middle name, Kitchener, is interesting. The year 1914 also marked the beginning of World War I, during which, Lord Kitchener, the British Secretary of War, was a popular hero in both Britain and Canada. It was as a gesture of support to Lord Kitchener that Dr Dahl was given the middle name, Kitchener. Within a year of moving to Canada, for what was most likely family reasons and the thinking on the parents part that their future children should be American citizens by birth (as documented in the book),2 the Dahl family moved back to the United States, this time, to Inwood, Iowa. The family added 2 more sons, Robert Alan Dahl and Roger Eugene Dahl. One of the earliest photographs of Dr Lewis Dahl, when he was 5 years old, is shown in Figure 1.Download figureDownload PowerPointFigure 1. Pictures of Dr Lewis K. Dahl (LKD)–Part 1. Arrows point to LKD. Top panel from left, Ca. 1919, LKD, 5 years, in Iowa with his younger brother Robert Dahl; ca. 1938, LKD, 16 years, in Skagway, Alaska basketball team; LKD working on the railroad project in Skagway, Alaska. Bottom panel from left, 24-year-old LKD with his brother Robert Dahl; Representative images of LKD pictured in the Alaskan wilderness enjoying his hobby of hunting for bears and mountain goats.Given the post-war era, living conditions for the family did not get any better in Iowa. Dr Peter Dahl was paid in kind for his services or at times not at all. A hard lifestyle is described,2 for example, in terms of the family having no heaters or firewood and having to live on drinking water collected from a neighbor's house. Vera had to heat well water for bathing on the kitchen stove with corn cobs given by patients as payment for treatment by Peter. These situations caused them to move once again to Skagway in Alaska, where Dr Lewis Dahl's father, Dr Peter Dahl, found employment as the physician for employees of the White Pass & Yukon Railroad. It is in this little town that Dr Lewis Dahl spent almost all of his formative years. The pictures shown in Figure 1 depict vivid images of the Dahl brothers getting attuned to hard work during summers on the railroad construction sites, playing basketball for the school team, and developing hobbies of hunting bears and mountain goats.After graduating from high school, Dr Lewis Dahl moved to Seattle, Washington, to complete his undergraduate studies at the University of Washington in 1935 (Figure 2). He then followed his dad's footsteps and obtained his MD degree from the University of Pennsylvania in 1939. During his Residency years at the Massachusetts General Hospital in Boston, the Second World War broke out and he took a break between 1942 and 1945 to serve as a Major in the US Army Medical Corps stationed in Australia and New Zealand (Figure 2). On his return, he completed his Residency and had choices to practice Internal Medicine or to take on research. His mentor at that time, Dr James Howard Means,4,5 was influential in Dr Dahl choosing the latter path as an Assistant in Medicine to conduct research in renal electrolyte physiology in the laboratory of Dr Donald Van Slyke (http://en.wikipedia.org/wiki/Donald_Van_Slyke), who is regarded as the Father of Clinical Chemistry (http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/van-slyke-donald.pdf). He then heard about the conversion of, what was at that time an Army barracks, into the present day Brookhaven National Laboratory on Long Island, NY, and he moved there to establish his own research laboratory.Download figureDownload PowerPointFigure 2. Pictures of Dr Lewis K. Dahl (LKD)–Part 2. Top panel from left, Arrow points to LKD, who is with his brother (ca. 1935) in a vessel bound for Seattle, Washington, for his undergraduate education; LKD, ca. 1945, serving as a Major in the US Army Medical Corps; November 12, 1949, LKD weds Marilyn Louise Cupp; Bottom panel from left, LKD with Marilyn and first child, Karen Dahl in Belmont, Long Island, NY, followed by 2 pictures of LKD during the days he was a Researcher at Brookhaven National Laboratory. (An interesting note: In the picture on the bottom panel right corner, he is holding an oosik of a Walrus).Other than his mentors, there are several important people who shaped his life. His brother, Robert Dahl, being only a year younger than him, appeared to have shared many of the intellectually formative experiences of Dr Dahl during their boyhood days. Although Lewis Dahl went on to make a mark in the medical field, Dr Robert Dahl earned his PhD in Political Science and was the Sterling Professor of Political Science at Yale University (http://en.wikipedia.org/wiki/Robert_A._Dahl).At the initial stages of his career as an independent researcher, he hired a technician into his laboratory, Ms. Marilyn Louise Cupp. Dr. Dahl eventually married her in 1949 (Figure 2). Among his close friends and colleagues, one name is prominent, who was with him until his death—Dr George Cotzias, a Greek-American Scientist (http://en.wikipedia.org/wiki/George_Cotzias). Dr Cotzias was the 1969 Laskar award recipient, who developed the method to clinically use L-DOPA, the metabolic precursor of dopamine to treat Parkinson's disease.6–9Dr Lewis Dahl was recognized for his outstanding contributions to the field of Hypertension3,10–25 with the Ciba Award (since known as the Novartis award and the Excellence in Hypertension Research award) in 1975. Unfortunately, Dr Dahl was diagnosed with multiple myeloma and he could not be present to receive the award, but received the award from his hospital bed. Three days later, on November 26, 1975, he passed away (http://www.bnl.gov/bnlweb/pubaf/bulletin/1947–1995/1975/05121975.pdf). Dr Dahl is survived by his wife, Marilyn, 3 daughters, Dr Karen Dahl, Mrs Margit Falk, Mrs Kristin Dahl, and 3 grandchildren, Kieran Dahl, Erika Lynn Dahl Bianchi, and Kyle Lewis Bianchi.Lewis Dahl and the Genesis of the Dahl RatsBeing the post-war era, the US Atomic Energy Commission was interested to conduct radiation-related research on populations in specific global research sites. Dr Dahl took advantage of the varied salt-consuming food habits of these populations and studied the relationship between salt and blood pressure.10,26 The data obtained was one of the early reports of a clear direct relationship between salt as an environmental factor and the extent of blood pressure in humans. Also in his early work, in 1948, with Kempner's rice–fruit diet for the treatment of hypertension, Dr Dahl and his colleagues demonstrated that the blood pressure lowering effect of the rice–fruit diet was primarily as a result of its low sodium content.27–29 If decreasing salt lowered hypertension, would increasing salt raise blood pressure?3 To test this directly, Dr Dahl raised Sprague–Dawley rats on differential salt diets and studied their blood pressure in response to salt.19 He observed that some, but not all, of the rats given a high-salt diet developed hypertension. This led to the interpretation that dietary salt could promote the development of hypertension only in rats that were genetically susceptible to salt-induced hypertension.16,17,30–38 Selective breeding of these rats produced animals, which are now called the Dahl salt-sensitive (S) rats. A contrasting program of selectively breeding rats that did not develop hypertension in response to a dietary high-salt regimen produced animals which are now called the Dahl salt-resistant (R) rats. Dr Dahl used these rats for various physiological studies.16,17,30–38 One such study that had an effect on the health of infants was the demonstration that feeding the formula milk used in the 1960s and 1970s caused mortality of the salt-sensitive hypertensive rats.11 This was attributed to the high salt content of the baby food formula.11 After his study was published, the US senate did its own investigation into this matter and issued a mandate for lowering salt in baby foods. In another classic study, Dr Dahl cross-transplanted kidneys between S and R rats and showed that the genetic makeup of the kidney was critical in controlling blood pressure.39Dahl Rats and the University of ToledoMuch of the work pertaining to the research on the inheritance of hypertension began in the 1970s with the inbreeding of the Dahl S and R rats at the University of Toledo College of Medicine (previously, Medical College of Ohio). How did the Dahl rats get to Toledo? Dr Lewis Dahl was collaborating with Dr John Paul Rapp on studying the relationship between steroidogenesis and hypertension40–46 and, before his death, yielded to the request by Dr Rapp for inheriting the Dahl rat models. Dr Rapp took the rats to the Penrose Research Laboratory for Comparative Pathology located on the grounds of the Philadelphia Zoological Society, where he was working at that time. Subsequently, when Dr Rapp was offered a faculty position at the Medical College of Ohio, he literally drove them up to Toledo (personal communication with Dr Rapp). After inbreeding,47 the rats were initially referred to as S/Jr and R/Jr rats (Jr stands for John Rapp). However, there was an unrelated strain previously named R, so the inbred Dahl rats bred by Dr Rapp have official designations of SS/Jr and SR/Jr for salt-sensitive and salt-resistant (http://rgd.mcw.edu/rgdweb/search/strains.html?term=salt&obj=strain). Informally, the strains are still more conveniently referred to as S and R. To this day, the original inbred colonies of the Dahl S and R rats are maintained in my laboratory at the University of Toledo College of Medicine and Life Sciences. Other colonies of the S rat, the most widely used one of which is the SS/JrHsdMcwi strain at the Medical College of Wisconsin (Mcwi), were established using the inbred S rats that were made commercially available by Dr Rapp in 1986 through the Harlan Laboratories, previously Harlan Sprague–Dawley (Hsd). For additional detailed history, please refer to the review by John Rapp.48 Besides the work presented here, which is mainly conducted in our Institution, other laboratories have also contributed significantly to delineating the genetics of hypertension using the S rat model.49–75 Among these are research groups from the Medical College of Wisconsin, who have used the S rat model and not only conducted mapping studies, but also developed several important resources for further studies using this model. These include the SS.BN consomic lines76–80 (http://pga.mcw.edu/) and, more recently, the generation of hundreds of targeted gene disrupted models on the genetic background of the S rat (http://rgd.mcw.edu/wg/physgenknockouts).Understanding the Genetics of Hypertension Through the Dahl Rat GenomeThrough the classic genetic approach of linkage analysis,48 the genome of the S rat was comparatively studied with the genomes of the R rat and 6 other inbred rat strains—Brown Norway, Lewis, Milan Normotensive rat, Wistar Kyoto rat, Albino Surgery, and the Spontaneously Hypertensive Rat.81–84 The specific crosses developed for linkage analyses are shown in Figure 3. Collectively, 16 distinct regions of the rat genome were recognized as quantitative trait loci, which are regions on the rat genome that are highly likely to contain genes that causally influence blood pressure84 (Figure 3). Subsequently, over the years, several iterations of substitution mapping were conducted. These mapping studies in our laboratory are at various stages ranging from successful positional mapping of novel genes85–87 and high resolution mapping to a few kilobases88,89 to larger genomic segments of several megabases.90–97 The positional mapping studies that have prioritized single candidate genes are given in Table. Two examples of such genes are Cyp11b1 on chromosome 785, 98 and Adamts16 on chromosome 186, 99, both of which contain coding sequence variants.Table. List of Genes Prioritized as Blood Pressure Quantitative Trait Genes by Positional Mapping Experiments Performed in Our Laboratory Using the Dahl S RatGeneProteinMechanismCyp11b111-β hydroxylaseSteroid biosynthesisAdamts16A disintegrin-like metalloproteinase with thrombospondin motifs-16UnknownRfflRififylinEndocytic recyclingNr2f2Nuclear receptor 2, factor 2Transcriptional regulationTmeff2Tomoregulin-2UnknownDownload figureDownload PowerPointFigure 3. Schematic diagram of blood pressure quantitative trait loci on the rat genome located by linkage analysis using rat populations shown in the inset. The number of the rat chromosome, which each gray cylinder represents, is given at the top. Yellow highlighted regions are approximate locations of the blood pressure QTL (quantitative trait loci) based on LOD plots obtained through linkage analysis conducted using the S rat as one of the parentals.One inconvenient truth about substitution mapping as a technique is that, regardless of the extent of high resolution even to the extent of a single gene, genomic segments which flank the candidate variant and additionally contain several other candidate variants that are often located within intergenic or intronic regions pose as confounding factors to arrive at definitive conclusions in favor of the suspect candidate variant. To overcome this limitation, targeted genetic engineering strategies have been applied. Such experiments have further prioritized a disintegrin-like metalloproteinase with thrombospondin motifs, 16 (Adamts16), as a genetic determinant of hypertension.100 Studies in 2 independent cohorts have added data to suggest the translational significance of this locus in human essential hypertension.86A second inconvenient truth is that high-resolution mapping studies are providing strong evidence to regions without variants in coding sequences as candidates for causing hypertension. Examples include a <81kb region on rat chromosome 988 and a <42.5kb region on rat chromosome 10.87,89 The region on chromosome 9 does not contain any gene annotations, but the region on chromosome 10 contains a single gene, Rififylin (Rffl), with no coding sequence variants.87 Both the transcript and protein forms of Rififylin were differentially expressed between the strains compared.87 Further, the function of Rififylin in cellular endocytic recycling was demonstrated to be linked to blood pressure regulation in the Dahl rats.87However, the precise variants responsible for the observed differential expression of Rififylin remain undiscovered. Comparative mapping of the rat genome with the mouse and human genomes indicates that there could be functional elements upstream of the Rffl gene, which are noncoding genomic elements influencing the expression of Rififylin (data unpublished). Such elements not being annotated on the rat genome is an impediment for progress in mapping of rat loci linked to blood pressure. These results are important as they are also of translational significance. For example, variants around the Rffl locus in humans, which are not coding sequence variants, are indeed linked to QT-intervals,101 which is the same phenotype observed in our substitution mapping studies linked to hypertension.87Another interesting candidate gene for hypertension in humans, Nuclear receptor 2, factor 2 (Nr2f2), was prioritized through a haplotype-based reanalysis of the Wellcome Trust Case Control Consortium study.102Nr2f2 was also a candidate gene prioritized through substitution-mapping studies using the Dahl S rat as one of the parental strains.103 A mutant Nr2f2 rat was generated using the zinc-finger nuclease technology, which suggests that Nr2f2 is indeed validated as a locus implicated in blood pressure control.104Although some of the above mentioned positional cloning studies with variants in protein-coding genes have contributed to our understanding of novel inherited factors implicated in the genesis of hypertension, other results obtained through continued genetic analysis of the Dahl rats are clearly indicative of a grossly underestimated complexity of the genomic blueprint of the genetics of hypertension. There is evidence for epistasis, that is, gene–gene interactions between mapped loci for blood pressure on the rat genome. Examples include epistasis between loci on 2 different chromosomes96,105 and loci that are closely linked on the same chromosome.92,106 For a modeling of epistasis with case-studies of experimental data obtained using the Dahl rat studies on the genetics of hypertension, readers are referred to a recent theoretical article.107PerspectivesDespite these inconvenient truths, the Dahl rat has been a powerful genetic model that has paved the way of our understanding of the contributions of genetics to the pathophysiological processes underlying the onset and progression of hypertension.48,68,85,87,100,108–110 Most of the research on the genetics of hypertension using the Dahl rat as an experimental model has focused on the autosomes. We have additionally reported the sequences of the mitochondrial genomes of S and R rats as being identical and therefore not contributing to the overall differences in blood pressure observed as a result of the selection process of these rat strains.111 Although we continue to further map the genome of the S rat for genetic elements regulating blood pressure, we have recently begun to use the Dahl rat model to investigate the importance of the gut microbiome in hypertension. Unpublished data does suggest that indeed interactions of the microbiota (and their microbiome) with the host genome are perhaps additional determinants that are important for the pathogenesis of hypertension.AcknowledgmentsSincere thanks to the Dahl family, especially Dr Karen Dahl, for providing many of the details on Dr Lewis Dahl that are documented in this article. Thanks to my mentor, John P. Rapp, for not only attending the Dahl Award Lecture but also for the thoughtful comments and proof reading of this article.Sources of FundingGrant support for our research (HL076709, HL112641, and HL020176) from the National Heart Lung and Blood Institute of the National Institutes of Health is gratefully acknowledged.DisclosuresNone.FootnotesCorrespondence to Bina Joe, Center for Hypertension and Personalized Medicine and Program in Physiological Genomics, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, 312, Block Health Science Bldg, 3000 Arlington Ave, Toledo, OH 43614. E-mail [email protected]References1. Morris BJ. Renin, genes, and beyond: 40 years of molecular discoveries in the hypertension field.Hypertension. 2011; 57:538–548. doi: 10.1161/HYPERTENSIONAHA.110.166967.LinkGoogle Scholar2. Dahl RAAfter the Gold Rush-Growing up in Skagway. United States of America: Xlibris Corporation; 2005.Google Scholar3. Dahl LK. 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