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The molecular basis of blood diseases
Mmrevlew 483
cytoplasm, because cytosolic factors (the signal recognition particle, accessory proteins. etc.) bind to the signal sequence as it emerges from the ribosome. Prevention of folding during synthesis and ATP-mediated posttranslational unfolding in the cytosol or on the target membrane would all contribute to keeping precursors in a loosely folded, translocation-competent state. In each instance. the precursor should only be able to refold once it has moved across a membrane. Although the free-energy
drop accompanying this refolding IS probably small, it may be the driving force for unidirectional movement of the precursor chain. Insertion of the presequence into the appropriate target membrane, ATP-mediated unfolding on the cytosolic side of the membrane, and lack of unfolding devices on the opposite membrane side might ensure that energy-yielding refolding drives translocation to completion.
Book Reviews Corning to Molecular with Blood
Terms
The Molecular Basis of Blood Diseases. Edited by G. Stamatoyannopoulos, A. W. Nienhuis, P. Leder, and P. W. Majerus. Philadelphia: W. B. Saunders Co. (1987). 747 pp. $95.00.
Although it is hazardous to predict the views of future historians of science, it seems clear that we are deeply immersed in the golden age of biology and medical science. This historical millennium is at least forty years old, perhaps dating from the studies of Avery, McLeod. and McCarty demonstrating that the transforming principle of bacteria is DNA. Nowadays we are becoming accustomed to learning about landmark additions to our knowledge of human biology and pathobiology every month or so. In the midst of this biomedical revolution The Molecular Basis of Blood Diseases is noteworthy and even a landmark publication itself. It represents one of a few efforts to synthesize available knowledge concerning an organ system of man- in this case the blood In fact. it is the successful integration of In?!tarials from such tradltionally separate disciplines as molecular genetics, cell biology, biochemistry, pathophysiology. and clinical medicine that makes this book so special. The Molecular Basis of Blood Diseases is divided into nineteen chapters, each written by one to three authors. The editors have chosen the subjects to be covered with care and have enlisted the services of outstanding contributors in each subdiscipline. In turn, these scientistauthors, often with considerable help from junior colleagues, have produced authoritative chapters on their subjects of expertise. The chapters are written to a consistently high standard. The writers have in common a broad interest in biology. No matter whether each is separately labeled a molecular biologist, X-ray crystallographer, pediatrician, etc., these authors are interested in both the basic and clinical implications of their work. This breadth of Interest helps to inte-
grate the diverse subject matter. Since the book covers subjects ranging from the role of the cytoskeleton in the contractile system of platelets and leukocytes through the structure-function analyses of hemoglobin to receptormediated endocytosis and the recycling of the transferrin receptor, it contarns a vast amount of new information for even the most seasoned scientist. After a useful chapter on methods of molecular genetics, which is noteworthy for its excellent illustrations, six chapters dealing with various aspects of hemoglobin are presented. These discuss globin gene structure and expression, hemoglobin switching, the thalassemias, molecular anatomy and physiology of hemoglobin, sickle cell disease, and iron metabolism. Although it is difficult to praise one or two of these chapters over the others, Perutz’s chapter on hemoglobin structure is particularly fascinating, from both scientific and historical viewpoints. One does not frequently find a highly regarded senior scientist like Perutz admit a misinterpretation of data and praise the work of another investigator who corrected the error. I also enjoyed the chapter on iron metabolism and the description of the travels of the transferrin receptor. The “hemoglobin” chapters are followed by a middle section of seven chapters dealing with immunology, oncogenesls, and disorders affecting leukocytes. The topics discussed are the immunoglobulin and Tcelt receptor genes, cellular and viral oncogenes, mechanisms of hematological neoplasms. T cell leukemia viruses, enzyme deficiencies in immunology. complement biology, and phagocytic disorders. Among these chapters the one on oncogenes, although long. is especially well organized and clearly wrltten. The third and last section of the book contains five chapters dealing with coagulation. These are on the prothrombin to thrombin conversion. the hemophilias and von Willeorand disease. fibrinogen, fibrinolysis, and platelets. I particularly enjoyed the one of fibrinolysis, with its clear description of the role of tissue plasminogen activator. Taken as a whole, the discussions are comprehensive and filled with helpful, high-quality illustrations. In a number of instances the same material is covered in two different chapters, but these duplications will be useful to the
Cell 484
reader Interested in several specific topics, and they are well cross-referenced. In addltton, each chapter contains a comprehensive reference list to pertinent literature, some appearing as recently as 1986. In that regard nearly all the chapters are as current as possible for a book of this magnitude. One exception is the discussion on HTLV3 and AIDS in the chapter on T cell leukemia viruses. Inform mation about this virus and its consequences has moved in a short time well beyond that which is presented. Although the book maintains a consistent high quality. it could be improved. A few chapters would have benefited from better proofreading. This minor distraction is highlighted by the error-free nature of most chapters, even the longer ones. Furthermore, a few chapters could have been shortened. In general, chapter length tends to correlate directly with the number of subjects covered and inversely with the amount of definitive knowledge available in the field-it takes more space to discuss conflicting theories than to write about accepted “fact.” Even so, some judicious editing in the style of a journal editor would have improved the book. Because of the wide range of material presented, anyone interested in human biology will obtain important new information from this book. The work will be of special interest to scientists working on blood components, human genetjcists, human cell and molecular biologists, hematologists, and oncologists. I look forward to the appearance of similarly integrated, highly scientific textbooks in other subspecialties of medicine. For me, The Molecular Basis of Blood Diseases makes a strong case for the medical curriculum pioneered my Case-Western Reserve University, which emphasizes an organ-system approach to medical school teaching. This book should be a wonderful text for an integrated hematology-oncology course. The editors, authors, and publishers are to be congratulated for a valuable addition to the medical and bioscience literature. Haig H. Kazazian, Jr. Department of Pediatrics Johns Hopkins University School and Johns Hopkins Hospital Baltimore, Maryland 21205
The Manipulative of Biologists Controlling Life: Ideal in Biology. By P. J. Pauly. New York: Oxford
of Medicine
Power
Jacques
Loeb
University
Press.
& the
(1987).
Engineering
252
pp. $24.95.
This extremely well written and well researched book provides a comprehensive history of one of biology’s most important figures. Jacques Loeb (1859-1924) is rightly regarded by author Philip Pauly as the father of the engi-
neering Ideal In biology-an ideal that has driven much of modern biology. By “engineering Pauly succinctly describes it.
shaped and ideal.” as
they [a number of nineteenth century blologlsts] envIsIoned manipulation, transformation, and creation of all the phenomena subsumed under the word “life” Nature was the raw material to be transformed by the power of the blologlst the appropriate image of the btologlst would be, not the naturalist. philosopher, or physicIan. but the engineer (p. 4) Although he became famous for his work in the United States on artificial parthenogenesis, Loeb was educated in Germany as a physician, receiving his M.D. in 1889. Unlike medical education in North America today, Loeb’s medical education in Germany tnvolved writing a research thesis; Loeb was. in effect, educated as a mechanistic physiologist. That his research was clearly tied to medicine was, I think, a significant causal factor in his adoption of the engineering conception of biology. This book is well worth reading as a history of an interesting and influential man. However, Jacques Loeb and his conception of biology have reached into modern biology and influenced the modern understanding of the purpose of biological science. This legacy of Loeb is seen in modern biological science in the importance accorded to research on the manipulation, transformation. and creation of organ&ms. For example, recombinant DNA research, hormone manipulation, and biochemical (pharmacological) intervention are integral parts of modern biological science. Hence any attempt to understand modern biology will be enriched by an understanding of Jacques Loeb’s views and contributions. The extent of the impact of Loeb’s engineering conception of biology on modern biology can be effectively illustrated, I think, by reference to an insight that I gained from reading Pauly’s book into a problem that has perpetually vexed me. I have for some time grappled with the fact that a large number of biologists are essentially ignorant of the details of evolutionary theory. Indeed. a large number have never taken a course in evolution. This has struck me as a stark contrast to physicists, most of whom have a detailed knowledge of Newtonian mechanical theory, the special theory of relativity, quantum theory, and so on. A number of unsatisfactory explanations have been offered for this contrast, the most simplistic being that biology in comparison with physics is not very mathematically sophisticated. Less simplistically, some would argue that the subject matter of biology is considerably more complex than that of physics, but this is simply false. The phenomena of physics and biology are extremely and equally complex. Consider, for example, objects cascading down a hill In a landslide. Even describing the behavior of one object would be a complex task-the explanation of the temporal sequence of movements of the multitude of interacting objects over time would be impossible. That is why in both biology and physics, what is studied are highly restricted phenomenon. Experiments in both disciplines are designed such that a very restricted set of parameters can be observed and measured; for example, individual balls are rolled down inclined planes,
cytoplasm, because cytosolic factors (the signal recognition particle, accessory proteins. etc.) bind to the signal sequence as it emerges from the ribosome. Prevention of folding during synthesis and ATP-mediated posttranslational unfolding in the cytosol or on the target membrane would all contribute to keeping precursors in a loosely folded, translocation-competent state. In each instance. the precursor should only be able to refold once it has moved across a membrane. Although the free-energy
drop accompanying this refolding IS probably small, it may be the driving force for unidirectional movement of the precursor chain. Insertion of the presequence into the appropriate target membrane, ATP-mediated unfolding on the cytosolic side of the membrane, and lack of unfolding devices on the opposite membrane side might ensure that energy-yielding refolding drives translocation to completion.
Book Reviews Corning to Molecular with Blood
Terms
The Molecular Basis of Blood Diseases. Edited by G. Stamatoyannopoulos, A. W. Nienhuis, P. Leder, and P. W. Majerus. Philadelphia: W. B. Saunders Co. (1987). 747 pp. $95.00.
Although it is hazardous to predict the views of future historians of science, it seems clear that we are deeply immersed in the golden age of biology and medical science. This historical millennium is at least forty years old, perhaps dating from the studies of Avery, McLeod. and McCarty demonstrating that the transforming principle of bacteria is DNA. Nowadays we are becoming accustomed to learning about landmark additions to our knowledge of human biology and pathobiology every month or so. In the midst of this biomedical revolution The Molecular Basis of Blood Diseases is noteworthy and even a landmark publication itself. It represents one of a few efforts to synthesize available knowledge concerning an organ system of man- in this case the blood In fact. it is the successful integration of In?!tarials from such tradltionally separate disciplines as molecular genetics, cell biology, biochemistry, pathophysiology. and clinical medicine that makes this book so special. The Molecular Basis of Blood Diseases is divided into nineteen chapters, each written by one to three authors. The editors have chosen the subjects to be covered with care and have enlisted the services of outstanding contributors in each subdiscipline. In turn, these scientistauthors, often with considerable help from junior colleagues, have produced authoritative chapters on their subjects of expertise. The chapters are written to a consistently high standard. The writers have in common a broad interest in biology. No matter whether each is separately labeled a molecular biologist, X-ray crystallographer, pediatrician, etc., these authors are interested in both the basic and clinical implications of their work. This breadth of Interest helps to inte-
grate the diverse subject matter. Since the book covers subjects ranging from the role of the cytoskeleton in the contractile system of platelets and leukocytes through the structure-function analyses of hemoglobin to receptormediated endocytosis and the recycling of the transferrin receptor, it contarns a vast amount of new information for even the most seasoned scientist. After a useful chapter on methods of molecular genetics, which is noteworthy for its excellent illustrations, six chapters dealing with various aspects of hemoglobin are presented. These discuss globin gene structure and expression, hemoglobin switching, the thalassemias, molecular anatomy and physiology of hemoglobin, sickle cell disease, and iron metabolism. Although it is difficult to praise one or two of these chapters over the others, Perutz’s chapter on hemoglobin structure is particularly fascinating, from both scientific and historical viewpoints. One does not frequently find a highly regarded senior scientist like Perutz admit a misinterpretation of data and praise the work of another investigator who corrected the error. I also enjoyed the chapter on iron metabolism and the description of the travels of the transferrin receptor. The “hemoglobin” chapters are followed by a middle section of seven chapters dealing with immunology, oncogenesls, and disorders affecting leukocytes. The topics discussed are the immunoglobulin and Tcelt receptor genes, cellular and viral oncogenes, mechanisms of hematological neoplasms. T cell leukemia viruses, enzyme deficiencies in immunology. complement biology, and phagocytic disorders. Among these chapters the one on oncogenes, although long. is especially well organized and clearly wrltten. The third and last section of the book contains five chapters dealing with coagulation. These are on the prothrombin to thrombin conversion. the hemophilias and von Willeorand disease. fibrinogen, fibrinolysis, and platelets. I particularly enjoyed the one of fibrinolysis, with its clear description of the role of tissue plasminogen activator. Taken as a whole, the discussions are comprehensive and filled with helpful, high-quality illustrations. In a number of instances the same material is covered in two different chapters, but these duplications will be useful to the
Cell 484
reader Interested in several specific topics, and they are well cross-referenced. In addltton, each chapter contains a comprehensive reference list to pertinent literature, some appearing as recently as 1986. In that regard nearly all the chapters are as current as possible for a book of this magnitude. One exception is the discussion on HTLV3 and AIDS in the chapter on T cell leukemia viruses. Inform mation about this virus and its consequences has moved in a short time well beyond that which is presented. Although the book maintains a consistent high quality. it could be improved. A few chapters would have benefited from better proofreading. This minor distraction is highlighted by the error-free nature of most chapters, even the longer ones. Furthermore, a few chapters could have been shortened. In general, chapter length tends to correlate directly with the number of subjects covered and inversely with the amount of definitive knowledge available in the field-it takes more space to discuss conflicting theories than to write about accepted “fact.” Even so, some judicious editing in the style of a journal editor would have improved the book. Because of the wide range of material presented, anyone interested in human biology will obtain important new information from this book. The work will be of special interest to scientists working on blood components, human genetjcists, human cell and molecular biologists, hematologists, and oncologists. I look forward to the appearance of similarly integrated, highly scientific textbooks in other subspecialties of medicine. For me, The Molecular Basis of Blood Diseases makes a strong case for the medical curriculum pioneered my Case-Western Reserve University, which emphasizes an organ-system approach to medical school teaching. This book should be a wonderful text for an integrated hematology-oncology course. The editors, authors, and publishers are to be congratulated for a valuable addition to the medical and bioscience literature. Haig H. Kazazian, Jr. Department of Pediatrics Johns Hopkins University School and Johns Hopkins Hospital Baltimore, Maryland 21205
The Manipulative of Biologists Controlling Life: Ideal in Biology. By P. J. Pauly. New York: Oxford
of Medicine
Power
Jacques
Loeb
University
Press.
& the
(1987).
Engineering
252
pp. $24.95.
This extremely well written and well researched book provides a comprehensive history of one of biology’s most important figures. Jacques Loeb (1859-1924) is rightly regarded by author Philip Pauly as the father of the engi-
neering Ideal In biology-an ideal that has driven much of modern biology. By “engineering Pauly succinctly describes it.
shaped and ideal.” as
they [a number of nineteenth century blologlsts] envIsIoned manipulation, transformation, and creation of all the phenomena subsumed under the word “life” Nature was the raw material to be transformed by the power of the blologlst the appropriate image of the btologlst would be, not the naturalist. philosopher, or physicIan. but the engineer (p. 4) Although he became famous for his work in the United States on artificial parthenogenesis, Loeb was educated in Germany as a physician, receiving his M.D. in 1889. Unlike medical education in North America today, Loeb’s medical education in Germany tnvolved writing a research thesis; Loeb was. in effect, educated as a mechanistic physiologist. That his research was clearly tied to medicine was, I think, a significant causal factor in his adoption of the engineering conception of biology. This book is well worth reading as a history of an interesting and influential man. However, Jacques Loeb and his conception of biology have reached into modern biology and influenced the modern understanding of the purpose of biological science. This legacy of Loeb is seen in modern biological science in the importance accorded to research on the manipulation, transformation. and creation of organ&ms. For example, recombinant DNA research, hormone manipulation, and biochemical (pharmacological) intervention are integral parts of modern biological science. Hence any attempt to understand modern biology will be enriched by an understanding of Jacques Loeb’s views and contributions. The extent of the impact of Loeb’s engineering conception of biology on modern biology can be effectively illustrated, I think, by reference to an insight that I gained from reading Pauly’s book into a problem that has perpetually vexed me. I have for some time grappled with the fact that a large number of biologists are essentially ignorant of the details of evolutionary theory. Indeed. a large number have never taken a course in evolution. This has struck me as a stark contrast to physicists, most of whom have a detailed knowledge of Newtonian mechanical theory, the special theory of relativity, quantum theory, and so on. A number of unsatisfactory explanations have been offered for this contrast, the most simplistic being that biology in comparison with physics is not very mathematically sophisticated. Less simplistically, some would argue that the subject matter of biology is considerably more complex than that of physics, but this is simply false. The phenomena of physics and biology are extremely and equally complex. Consider, for example, objects cascading down a hill In a landslide. Even describing the behavior of one object would be a complex task-the explanation of the temporal sequence of movements of the multitude of interacting objects over time would be impossible. That is why in both biology and physics, what is studied are highly restricted phenomenon. Experiments in both disciplines are designed such that a very restricted set of parameters can be observed and measured; for example, individual balls are rolled down inclined planes,