- Email: [email protected]
On the Origin of Genetics and Beginnings of Medical Genetics of Diseases of the Kidney
HISTORY
On the Origin of Genetics and Beginnings of Medical Genetics of Diseases of the Kidney Garabed Eknoyan The twentieth century has been termed the century of the gene. Although the term “gene” was introduced in 1909, interest in reproduction and heredity has occupied humankind since its transition from hunter-gatherers to farmers and herders. Heredity, as it applies to diseases, began with Greek medicine. The humoral theory of the Hippocratic Corpus provided an etiological explanation for susceptibility of individuals to certain diseases well into the nineteenth century and was variously termed diathesis, temperament, and constitution. The application of the new probability math to quantify the hybridization of sweet peas by Gregor Mendel (1822-1884) in 1866 provided a scientific basis to inheritance, which had theretofore been an amalgam of scattered empirical observations. The near simultaneous publication of Origin of Species by Charles Darwin (1809-1882) in 1859 was a key catalyst in the transfer of what had been studies in plant biology into studies of populations and humans. The subsequent growth of genetics has been the outcome of interplay of technological breakthroughs in statistical analysis, cytology, biochemistry, physics, and computer science, coupled with the insightful analysis of workers in the field, several of whom have been the recipients of the Nobel Prize in medicine or chemistry since 1933. Application of these techniques to molecular biology and medical genetics is just beginning to yield insight into diseases of the kidney and provide visions of their likely therapies in the future. © 2006 by the National Kidney Foundation, Inc. Index Words: Gregor Mendel; Bright’s disease; History of genetics; Genetics of kidney disease; Diathesis; Pangenesis
N
o branch of medicine has been as broadly encompassing or developed as extensively and rapidly as genetics. What started as relatively isolated experimental observations in biology in the nineteenth century made its entrance into medicine and exploded in the past century, which has come to be dubbed aptly “The century of the gene.” 1Whereas the term “genetics” was introduced only in 1906 and “genes” in 1909, reproduction and heredity have preoccupied humankind for a long time. Observations on the transmission of selected features and characteristics from one generation to another began with the domestication of animals and cultivation of plants during the transition of humans from huntergatherers to farmers and herders. By the time settlements, city-states, and empires began to be established in the river civilizations of the Middle East, information accrued from trialand-error observations of the preceding mil-
From the Renal Section, Department of Medicine, Baylor College of Medicine, Houston, TX Address correspondence to G. Eknoyan, MD, Department of Medicine (523-D), Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail :[email protected] © 2006 by the National Kidney Foundation, Inc. 1548-5595/06/1302-0013$32.00/0 doi:10.1053/j.jackd.2006.01.004
174
lennia of transition had developed into a body of knowledge that was preserved, transmitted, practiced, and productively exploited throughout antiquity (Fig 1). Whereas the oldest traditions refer mostly to selection characteristics of domesticated animals and cultivated plants, the relation of somatologic variations to health and disease had not escaped attention. The ancient Greeks began to focus on problems of heredity as they apply to humans in general and to diseases in particular. The Hippocratic Corpus (fifth to third century B.C.) specifically comments on the inheritance of certain temperaments and their association with specific illnesses.2,3 The humoral theory of the Hippocratic Corpus, in which the relative dominance of the four humors determined the constitution of the body, provided an etiological explanation for the susceptibility of individuals to certain diseases designated as “diathesis,” a term that Galen (131-200) replaced with “temperament.”4 For the subsequent 16 centuries, temperament was used to refer to the predisposition of individuals to specific disorders until the nineteenth century, when diathesis gained transient popularity again until its replacement with constitution thereafter.4 – 8 Beginning with their philosophical analysis
Advances in Chronic Kidney Disease, Vol 13, No 2 (April), 2006: pp 174-177
Origin of Genetics
175
Origins: Plant Biology
Figure 1. Stone panel from the Northwest Palace of Ashurnasirpal II, Nimrud, Assyria (ca. 880 B.C.). Bird-headed creatures holding buckets and cones artificially pollinating the so-called sacred tree. (Reprinted with permission. Photo credit: HIP/Art Resource, NY. British Museum, London, UK.)
of nature, the ancients Greeks concluded semen transmitted hereditable traits. Plato (428347 B.C.), who in his writings lays the rudiments of eugenics—a term not coined until 1883—in his account of the creation of man in Timaeus, considers the head the most sacred part of the body and the site where semen is formed and transmitted through the spinal cord to the testicles. Hippocrates (459-355 B.C.), on the other hand, considered the semen to be formed from the essence of every part of the body, and then traveled in the vessels to the testicles, which serve merely as passages. This notion of “pangenesis” survived in different guises well into the nineteenth century and was used by Charles Darwin (1809-1882), whose contributions beginning with The Origin of Species (1859) was a key catalyst in the transfer of what had been studies in plant biology into studies of populations and humans.2– 6 Through the centuries, the fundamentals of the pangenesis doctrine—as fluids or forces derived from the entire body—formed the basis of a number of hypothesis until they were challenge by August Weisman (18341914), who proposed the concept of particulate constituents as the substance transmitted from parents to offspring. He gave this substance the name “germ-plasm.” 9 What germplasm was and where it came from had to await clarification from studies in biology.
The experience of farmers and herders, who had been selectively breeding their plants and animals to produce more useful hybrids, remained an amalgam of scattered empirical observations concerning inheritance well into the eighteenth century. The discovery that higher plants have sexual reproduction and that pollen represents the male element, in the closing years of the seventeenth century, provided experimental investigators a new stimulus for crossbreeding and the systematic study of plant hybrids.2,3 By the time the Augustinian friar Gregor Mendel (1822-1884) began his experiments, botany and the study of hybridization was an established science, with academic departments in most European universities. At the University of Vienna, at the urging of his equally scientifically inclined Abbot, Mendel studied not only botany but also zoology, physics, chemistry, and mathematics. His application of mathematics to quantitatively express his results distinguished his article on peas, which had been studied and reported previously, including the changes that occur in second and third generations, but only as descriptive empiric observations.10,11 The new “numerical method” (probability math) was just beginning to be applied to medicine and the biological sciences.12 Mendel applied the numerical method to his studies. Its very novelty may have been one reason that the importance of his studies failed to capture the attention of the 40 experts to whom Mendel sent reprints of his article in 1866.10 As plant hybridization studies progressed over the ensuing decades, the changes gradually came to be seen not as a random phenomenon but as one that followed mathematical laws that could be proved experimentally. Mendel’s work was “rediscovered” independently by three biologists: Hugo de Vries (1848-1935) in Holland, Carl Correns (18641933) in Germany, and Erich von Tschermark (1871-1952) in Austria. All acknowledged Mendel simultaneously in their presentations and publications in the same volume of the Proceedings of the German Botanical Society in 1900.1,4,9,10 The subsequent work and championing of Mendel by William Bateson (1861-
176
Garabed Eknoyan
1926) in England brought to Mendel the credit he deserved.10 Bateson, who introduced the term genetics, was instrumental in the subsequent growth of this new science. Apart from his own experimental studies, his strong mathematical inclination led to his association with Karl Pearson (1857-1936), a founding father of medical statistics and its application to genetic analysis. At the same time, Francis Galton (1822-1911), a cousin of Darwin who coined the term eugenics, introduced quantitative measurement of populations to the study of genetics. Galton’s fundamental work on biostatistics had a major influence on the subsequent evolution of population studies and statistical methods.12 Also, Bateson’s clinical interests led him to support the work of Archibald Garrod (1857-1935) on alkaptonuria, the first inherited disease to which the new laws of inheritance were applied.10,11
Coming of Age: Genetics The subsequent growth of genetics benefited from technical advances other than statistics. First among those advances was the melding of cytology and genetics that was to allow for the visualization of the particulate matters of inheritance that had been termed germ-plasm by Weisman, elemente by Mendel, gemules by Darwin, and, ultimately, genes by Wilhelm Johannsen (1857-1927) in 1909. They were located in the nucleus by Ernst Haeckel (1834-1919) in 1866, shown to consist of nucleic acid by Friederich Miescher (1844-1895) in 1871, and located on the threadlike chromosomes by Thomas H. Morgan (1866-1945) in 1911, which resulted in the Nobel Prize for his work on genetics, in 1933.1– 4 The century of genetics was now launched. Its subsequent progress has been a combination of technological breakthroughs and insightful analysis by workers in the field, several of whom became Nobel laureates. 13 Perhaps most notable of these workers are James Watson (b. 1928) and Francis Crick (19162004), for elucidating the structure of DNA, a remarkably simple mechanism that allows for the capacity of self-replication and explains the stability of inheritance,1 and, from the perspective of nephrology, Peter Agre (b.1949), for the discovery of water channels.14
Beginnings: Medical Genetics of Kidney Disease The application of molecular biology to those early structural observations and its many breakthroughs (recombinant DNA technology, transcription analysis restriction enzymes, reverse transcriptase, and DNA sequencing) were crowned at the turn of the century by the completion of the Human Genome Project. Application of these techniques to molecular pathophysiology led to the identification of several membrane channels and the identification of diverse membrane transporters for sodium, potassium, chloride, hydrogen, and other elements. Mutations of these channels, or transporters, account for the syndromes described in this issue of Advances in Chronic Kidney Disease. Not discussed in this issue but an early and prime beneficiary of recombinant technology has been erythropoietin. As impressive as these results have been, they are just the tip of the iceberg and merely herald things to come, such the use of stem cells to repair injured kidneys15 and the potential for kidney-tissue engineering.16 No doubt future studies will provide additional answers and even therapies for the progression of chronic kidney disease to end-stage renal disease. Ironically, the man whose work opened this Pandora’s box, Mendel, died from what was then diagnosed as Bright’s disease, the eponymous malady of one of his contemporaries, Richard Bright (1789-1858), who, in turn, opened the box of diseases of the kidney.17
References 1. Keller EF: The century of the gene. Harvard University Press, Cambridge, MA, 2000 2. Stubbe H: History of genetics: From prehistoric times to the rediscovery of Mendel’s laws. Cambridge, MIT Press, MA, 1972 3. Sturtevant AH: A history of genetics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2001 4. Olby RC: Constitutional and hereditary disorders. In Bynum WF, Porter R, eds: Companion Encyclopedia of the History of Medicine. Routledge, London, UK, 1997, pp 412-437 5. Ackernecht EH: Diathesis. The word and the concept in medical history. Bull Hist Med 56:317-325, 1982 6. Olby R: The emergence of genetics. In Olby RC, Cantor GN, Christie JRR, Hodge MJ, eds. Companion to the History of Modern Science. Routledge, London, UK, 1996. pp 521-536 7. Hutchinson J: The pedigree of disease: Being six lec-
Origin of Genetics
8. 9.
10.
11. 12.
tures on temperament, idiosyncracy and diathesis delivered in the theatre of the Royal College of Surgeons 1881. W. Wood & Co., New York, NY, 1885 Ciocco A: The historical background of the modern study of constitution. Bull Hist Med 4:23-38, 1936 Dunn LC: A short history of genetics. The development of the main lines of thought 1864-1939. Iowa State University Press, Ames, IA, 1965 Keynes M, Edwards AWF, Peel RC: A century of Mendelism in human genetics. CRC Press, Boca Raton, FL, 2004 Gliboff S: Gregor Mendel and the laws of evolution. Hist Sci 37:217-235, 1999 Eknoyan G: Emergence of quantification in clinical investigation and the quest for certainty in therapeu-
13.
14. 15.
16.
17.
177
tics. The road from Hammurabi to Kefauver. Adv Chronic Kidney Dis 12:88-95, 2005 Baltimore D: Nobel lectures in molecular biology 1933-1975. Elsevier North-Holland, New York, NY, 1977 Agre P: Aquaporin water channels in kidney. J Am Soc Nephrol 11:764-777, 2000 Cantley LG: Adult stem cells in the repair of the injured renal tubule. Nat Clin Pract Nephrol 1:22-31, 2005 Steer DI, Nigam SK: Developmental approaches to kidney tissue engineering. Am J Physiol Renal Physiol 286:F1-F7, 2004 Sajner J: Gregor Mendels krakenheit und tod. Sudhoffs Arch Gesch Med Naturwiss 47:377-382, 1963
On the Origin of Genetics and Beginnings of Medical Genetics of Diseases of the Kidney Garabed Eknoyan The twentieth century has been termed the century of the gene. Although the term “gene” was introduced in 1909, interest in reproduction and heredity has occupied humankind since its transition from hunter-gatherers to farmers and herders. Heredity, as it applies to diseases, began with Greek medicine. The humoral theory of the Hippocratic Corpus provided an etiological explanation for susceptibility of individuals to certain diseases well into the nineteenth century and was variously termed diathesis, temperament, and constitution. The application of the new probability math to quantify the hybridization of sweet peas by Gregor Mendel (1822-1884) in 1866 provided a scientific basis to inheritance, which had theretofore been an amalgam of scattered empirical observations. The near simultaneous publication of Origin of Species by Charles Darwin (1809-1882) in 1859 was a key catalyst in the transfer of what had been studies in plant biology into studies of populations and humans. The subsequent growth of genetics has been the outcome of interplay of technological breakthroughs in statistical analysis, cytology, biochemistry, physics, and computer science, coupled with the insightful analysis of workers in the field, several of whom have been the recipients of the Nobel Prize in medicine or chemistry since 1933. Application of these techniques to molecular biology and medical genetics is just beginning to yield insight into diseases of the kidney and provide visions of their likely therapies in the future. © 2006 by the National Kidney Foundation, Inc. Index Words: Gregor Mendel; Bright’s disease; History of genetics; Genetics of kidney disease; Diathesis; Pangenesis
N
o branch of medicine has been as broadly encompassing or developed as extensively and rapidly as genetics. What started as relatively isolated experimental observations in biology in the nineteenth century made its entrance into medicine and exploded in the past century, which has come to be dubbed aptly “The century of the gene.” 1Whereas the term “genetics” was introduced only in 1906 and “genes” in 1909, reproduction and heredity have preoccupied humankind for a long time. Observations on the transmission of selected features and characteristics from one generation to another began with the domestication of animals and cultivation of plants during the transition of humans from huntergatherers to farmers and herders. By the time settlements, city-states, and empires began to be established in the river civilizations of the Middle East, information accrued from trialand-error observations of the preceding mil-
From the Renal Section, Department of Medicine, Baylor College of Medicine, Houston, TX Address correspondence to G. Eknoyan, MD, Department of Medicine (523-D), Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail :[email protected] © 2006 by the National Kidney Foundation, Inc. 1548-5595/06/1302-0013$32.00/0 doi:10.1053/j.jackd.2006.01.004
174
lennia of transition had developed into a body of knowledge that was preserved, transmitted, practiced, and productively exploited throughout antiquity (Fig 1). Whereas the oldest traditions refer mostly to selection characteristics of domesticated animals and cultivated plants, the relation of somatologic variations to health and disease had not escaped attention. The ancient Greeks began to focus on problems of heredity as they apply to humans in general and to diseases in particular. The Hippocratic Corpus (fifth to third century B.C.) specifically comments on the inheritance of certain temperaments and their association with specific illnesses.2,3 The humoral theory of the Hippocratic Corpus, in which the relative dominance of the four humors determined the constitution of the body, provided an etiological explanation for the susceptibility of individuals to certain diseases designated as “diathesis,” a term that Galen (131-200) replaced with “temperament.”4 For the subsequent 16 centuries, temperament was used to refer to the predisposition of individuals to specific disorders until the nineteenth century, when diathesis gained transient popularity again until its replacement with constitution thereafter.4 – 8 Beginning with their philosophical analysis
Advances in Chronic Kidney Disease, Vol 13, No 2 (April), 2006: pp 174-177
Origin of Genetics
175
Origins: Plant Biology
Figure 1. Stone panel from the Northwest Palace of Ashurnasirpal II, Nimrud, Assyria (ca. 880 B.C.). Bird-headed creatures holding buckets and cones artificially pollinating the so-called sacred tree. (Reprinted with permission. Photo credit: HIP/Art Resource, NY. British Museum, London, UK.)
of nature, the ancients Greeks concluded semen transmitted hereditable traits. Plato (428347 B.C.), who in his writings lays the rudiments of eugenics—a term not coined until 1883—in his account of the creation of man in Timaeus, considers the head the most sacred part of the body and the site where semen is formed and transmitted through the spinal cord to the testicles. Hippocrates (459-355 B.C.), on the other hand, considered the semen to be formed from the essence of every part of the body, and then traveled in the vessels to the testicles, which serve merely as passages. This notion of “pangenesis” survived in different guises well into the nineteenth century and was used by Charles Darwin (1809-1882), whose contributions beginning with The Origin of Species (1859) was a key catalyst in the transfer of what had been studies in plant biology into studies of populations and humans.2– 6 Through the centuries, the fundamentals of the pangenesis doctrine—as fluids or forces derived from the entire body—formed the basis of a number of hypothesis until they were challenge by August Weisman (18341914), who proposed the concept of particulate constituents as the substance transmitted from parents to offspring. He gave this substance the name “germ-plasm.” 9 What germplasm was and where it came from had to await clarification from studies in biology.
The experience of farmers and herders, who had been selectively breeding their plants and animals to produce more useful hybrids, remained an amalgam of scattered empirical observations concerning inheritance well into the eighteenth century. The discovery that higher plants have sexual reproduction and that pollen represents the male element, in the closing years of the seventeenth century, provided experimental investigators a new stimulus for crossbreeding and the systematic study of plant hybrids.2,3 By the time the Augustinian friar Gregor Mendel (1822-1884) began his experiments, botany and the study of hybridization was an established science, with academic departments in most European universities. At the University of Vienna, at the urging of his equally scientifically inclined Abbot, Mendel studied not only botany but also zoology, physics, chemistry, and mathematics. His application of mathematics to quantitatively express his results distinguished his article on peas, which had been studied and reported previously, including the changes that occur in second and third generations, but only as descriptive empiric observations.10,11 The new “numerical method” (probability math) was just beginning to be applied to medicine and the biological sciences.12 Mendel applied the numerical method to his studies. Its very novelty may have been one reason that the importance of his studies failed to capture the attention of the 40 experts to whom Mendel sent reprints of his article in 1866.10 As plant hybridization studies progressed over the ensuing decades, the changes gradually came to be seen not as a random phenomenon but as one that followed mathematical laws that could be proved experimentally. Mendel’s work was “rediscovered” independently by three biologists: Hugo de Vries (1848-1935) in Holland, Carl Correns (18641933) in Germany, and Erich von Tschermark (1871-1952) in Austria. All acknowledged Mendel simultaneously in their presentations and publications in the same volume of the Proceedings of the German Botanical Society in 1900.1,4,9,10 The subsequent work and championing of Mendel by William Bateson (1861-
176
Garabed Eknoyan
1926) in England brought to Mendel the credit he deserved.10 Bateson, who introduced the term genetics, was instrumental in the subsequent growth of this new science. Apart from his own experimental studies, his strong mathematical inclination led to his association with Karl Pearson (1857-1936), a founding father of medical statistics and its application to genetic analysis. At the same time, Francis Galton (1822-1911), a cousin of Darwin who coined the term eugenics, introduced quantitative measurement of populations to the study of genetics. Galton’s fundamental work on biostatistics had a major influence on the subsequent evolution of population studies and statistical methods.12 Also, Bateson’s clinical interests led him to support the work of Archibald Garrod (1857-1935) on alkaptonuria, the first inherited disease to which the new laws of inheritance were applied.10,11
Coming of Age: Genetics The subsequent growth of genetics benefited from technical advances other than statistics. First among those advances was the melding of cytology and genetics that was to allow for the visualization of the particulate matters of inheritance that had been termed germ-plasm by Weisman, elemente by Mendel, gemules by Darwin, and, ultimately, genes by Wilhelm Johannsen (1857-1927) in 1909. They were located in the nucleus by Ernst Haeckel (1834-1919) in 1866, shown to consist of nucleic acid by Friederich Miescher (1844-1895) in 1871, and located on the threadlike chromosomes by Thomas H. Morgan (1866-1945) in 1911, which resulted in the Nobel Prize for his work on genetics, in 1933.1– 4 The century of genetics was now launched. Its subsequent progress has been a combination of technological breakthroughs and insightful analysis by workers in the field, several of whom became Nobel laureates. 13 Perhaps most notable of these workers are James Watson (b. 1928) and Francis Crick (19162004), for elucidating the structure of DNA, a remarkably simple mechanism that allows for the capacity of self-replication and explains the stability of inheritance,1 and, from the perspective of nephrology, Peter Agre (b.1949), for the discovery of water channels.14
Beginnings: Medical Genetics of Kidney Disease The application of molecular biology to those early structural observations and its many breakthroughs (recombinant DNA technology, transcription analysis restriction enzymes, reverse transcriptase, and DNA sequencing) were crowned at the turn of the century by the completion of the Human Genome Project. Application of these techniques to molecular pathophysiology led to the identification of several membrane channels and the identification of diverse membrane transporters for sodium, potassium, chloride, hydrogen, and other elements. Mutations of these channels, or transporters, account for the syndromes described in this issue of Advances in Chronic Kidney Disease. Not discussed in this issue but an early and prime beneficiary of recombinant technology has been erythropoietin. As impressive as these results have been, they are just the tip of the iceberg and merely herald things to come, such the use of stem cells to repair injured kidneys15 and the potential for kidney-tissue engineering.16 No doubt future studies will provide additional answers and even therapies for the progression of chronic kidney disease to end-stage renal disease. Ironically, the man whose work opened this Pandora’s box, Mendel, died from what was then diagnosed as Bright’s disease, the eponymous malady of one of his contemporaries, Richard Bright (1789-1858), who, in turn, opened the box of diseases of the kidney.17
References 1. Keller EF: The century of the gene. Harvard University Press, Cambridge, MA, 2000 2. Stubbe H: History of genetics: From prehistoric times to the rediscovery of Mendel’s laws. Cambridge, MIT Press, MA, 1972 3. Sturtevant AH: A history of genetics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2001 4. Olby RC: Constitutional and hereditary disorders. In Bynum WF, Porter R, eds: Companion Encyclopedia of the History of Medicine. Routledge, London, UK, 1997, pp 412-437 5. Ackernecht EH: Diathesis. The word and the concept in medical history. Bull Hist Med 56:317-325, 1982 6. Olby R: The emergence of genetics. In Olby RC, Cantor GN, Christie JRR, Hodge MJ, eds. Companion to the History of Modern Science. Routledge, London, UK, 1996. pp 521-536 7. Hutchinson J: The pedigree of disease: Being six lec-
Origin of Genetics
8. 9.
10.
11. 12.
tures on temperament, idiosyncracy and diathesis delivered in the theatre of the Royal College of Surgeons 1881. W. Wood & Co., New York, NY, 1885 Ciocco A: The historical background of the modern study of constitution. Bull Hist Med 4:23-38, 1936 Dunn LC: A short history of genetics. The development of the main lines of thought 1864-1939. Iowa State University Press, Ames, IA, 1965 Keynes M, Edwards AWF, Peel RC: A century of Mendelism in human genetics. CRC Press, Boca Raton, FL, 2004 Gliboff S: Gregor Mendel and the laws of evolution. Hist Sci 37:217-235, 1999 Eknoyan G: Emergence of quantification in clinical investigation and the quest for certainty in therapeu-
13.
14. 15.
16.
17.
177
tics. The road from Hammurabi to Kefauver. Adv Chronic Kidney Dis 12:88-95, 2005 Baltimore D: Nobel lectures in molecular biology 1933-1975. Elsevier North-Holland, New York, NY, 1977 Agre P: Aquaporin water channels in kidney. J Am Soc Nephrol 11:764-777, 2000 Cantley LG: Adult stem cells in the repair of the injured renal tubule. Nat Clin Pract Nephrol 1:22-31, 2005 Steer DI, Nigam SK: Developmental approaches to kidney tissue engineering. Am J Physiol Renal Physiol 286:F1-F7, 2004 Sajner J: Gregor Mendels krakenheit und tod. Sudhoffs Arch Gesch Med Naturwiss 47:377-382, 1963