- Email: [email protected]
Connective tissue and its heritable disorders: Molecular, genetic and medical aspects
MISCELLANEA
been made to emphasize details that are known to be critical for successful reconstitution, but that are often either not included or not obvious in the original published methods. My major criticism of these chapters is that they could benefit from more uniform use of simple diagrams to illustrate the system and its component parts, as well as diagrams for some of the techniques. The final section of this volume, 'Identification of transport intermediates', could be more readily called 'Purification and characterization of transport proteins'. Although four chapters describe methods for the isolation of transport vesicles and manipulations that can be used to define sequential intermediates in transport, the majority of the chapters present
The ECM: structure, function and dysfunction Connective Tissue and Its Heritable Disorders: Molecular, Genetic and Medical Aspects edited by PeterM. Royceand Beat Steinmann, Wiley.Liss, 1992. £185.00 (724 pages) ISBN471 588 199 In the last ten years, there has been enormous progress in our understanding of the extracellular matrix. The point that collagen is more than just 'glue' has been driven home many times. We now know that collagen comes in many types (types VI-XVII ha~e been characterized in the last decade), which have different tissue distributions and different fine structures. We have also learned that mutations in different collagen genes lead to different heritable disorders of connective tissue. And, significant progress has been made in identifying, characterizing and sequencing more than 25 additional noncollagenous inhabitants of the extracellular matrix. There have been reviews of many of these extracellular matrix compo-
methods for purifying and characterizing endogenous and recombinant transport-t'elated proteins. Unlike the earlier chapters, many of these protocols do not seem to contain significantly more information than is found in the original published methods. This section does, however, contain the only published protocol for purifying recombinant NSF, and a useful compendium of the seemingly limitless family of rab proteins. In summary, this volume is an excellent guide to the available systems for reconstitution of transport within the vacuolar system, both in yeast and mammalian cells, and to the transport-related proteins that have been identified to date. On the other hand, it does not really provide a coherent framework of
general considerations and methodology applicable to the design of such systems from scratch. What then is the purpose of this collection? I would like to think that it is more than just a monument to the ingenuity and skills of the scientists who developed these in vitro systems. Perhaps it is a sign that in vitro reconstitution of transport is 'coming of age' - making the transition from being a novelty to a tool available to all cell biologists, whether they are pioneers or not. This volume constitutes the first step in making this technology accessible. One hopes that this will lead to a second wave of innovation, as more energy is focused on the different aspects of transport that are amenable to dissection with these characterized systems.
nents and of connective tissues like skin and cartilage, and an excellent book on the cell biology of the extracellular matrix has been recently updated 1. Connective Tissue and Its Heritable Disorders is a kind of compendium, intended to 'be of benefit not only to clinical and associated personnel, but also to basic scientists for whom the juxtaposition of basic and clinical reviews within one set of covers might aid an enhanced awareness of the functional significance of the molecules they are studying.' The concept of heritable disorders of connective tissue was originally developed by Victor MCKusick (whose last edition of Heritable Disorders of Connective Tissue appeared 20 years ago) in relation to the Marfan syndrome, and then extended to include osteogenisis imperfecta (OI), the Ehlers-Danlos syndrome (EDS), pseudoxanthoma elasticum, cutis laxa, the mucopolysaccharidoses, the chondro.. dysplasias, fibrodysplasia ossificans progressiva, and disorders like homocystinuria, alkaptonuria and Menkes syndrome, which can secondarily affect the connective tissue. The latter half of Connective Tissue and Its Heritable Disorders contains chapters on each of these classical disorders. The molecular bases of Marfan syndrome, OI, some subtypes of EDS and some chondrodysplasias have now been identified and are well reviewed in this book. These include molecular abnormalities in
type I, II and III collagens and in more recently characterized extracellular matrix molecules. In addition, the editors have included chapters on epidermolysis bullosa, disorders of keratinization, prolidase deficiency, (xl-antitrypsin deficiency, osteopetrosis and heritable rickets. The first half of the text is composed of chapters on the biology of the extracellular matrix, including reviews of connective tissue morphology (skin and tendon, cartilage and bone), molecules (collagens, elastin, glycosylated matrix proteins, adhesive glycoproteins and keratins), bone biology and extracellular matrix degradation. Each of these chapters collates current information in a readable fashion. The heritable disorders of connective tissues were first classified as such by their visible dramatic effects upon tissues like skin (soft and rubbery in EDS; loose in curls laxa) and bone (brittle and easily broken in OI; excessively long in the Marfan syndrome; short in the chondrodysplaslas), which contain large amounts of ECM. Nowadays, with increased knowledge o| the molecular components of the ECM, the classification of heritable disorders of connective tissue will be continually expanded _~s molecular defects in these components are discovered in genetic diseases. For example, MCKusick suggests in his introduction that Stickler syndrome and Alport syndrome might warrant separate chapters, since these
TRENDS IN CELL BIOLOGY VOL. 3 OCTOBER 1993
Peggy Wiedman Saint Louis University Medical Center, 1402 South Grand Boulevard, St Louis, MO 63104, USA.
361
MISCELLANEA
Lynn Y. Sakai ShrinersHospital for Crippled Children, Departmentof Biochemist~ and Molecular Biology, Oregon Health Sciences University, Portland, OR, USA.
syndromes are associated with defects in type II collagen (Stickler) and type IV collagen (Alport). The recent discovery of a translocation disruption of the elastin gene in families with the inherited disease supravalvular aortic stenosisz might now also qualify this disorder for an individual chapter. Moreover, as additional components of the extracellular matrix are discovered and characterized, new candidate genes for inherited diseases will become available. This has been demonstrated recently in the cases of type VII collagen3 and epidermolysis bullosa dystrophica"~, and fibrillin s and the Marfan syndrome6. This book is both a timely and a comprehensive resource. It communicates the growing complexity of the extracellular matrix and the expansion of knowledge of the heritable disorders of connective tissue. Progress on heritable disorders has been driven by the integration of developments in basic research with clinical investigations, and this is reflected here in the inclusion of reviews on both basic research and clinical aspects.
Curing the PhD blues Postgraduate Study in the Biological Sciences: A Researcher's Companion
Catherine Brookshank Trends in Biochemical Sciences
362
by Robert J. Beynon, Portland Press, 1993. £9.50 (xi + 151 pages) aSBN 1 85578 009 7
This little book is a rnust for anyone starting out on a career in research. Its nine sympathetically written chapters offer sound advice on every
It is appropriate that Royce and Steinmann offer this book as an aid to 'enhanced awareness' by research scientists of the functional significance of the molecules they study. Scientists interested in bone, for example, might also read about fibrodysplasia ossificans progressiva and come up with interesting ideas regarding its etiology. These days, however, it is equally likely that scientists interested in particular components will employ every available technology to determine the functional significance of their molecules, and these technologies may themselves generate the hypotheses relevant to human disease. We have already seen the utility of this approach in, for example, the comparison of the effects of engineered mutant keratin with epidermolysis bullosa simplexz. Similar functional studies are underway for most of the extracellular matrix molecules reviewed in this book. For some of these molecules, engineered mutations may result in phenotypes resembling the classical heritable disorders of connective tissue or other inherited diseases that could
become classified as such. My only criticism of the book is that, for basic scientists interested in the exploitation of new technologies to study function, there is little emphasis placed on the available examples and the potential of these technologies for contributing to the under. standing of human disease.
aspect of doing a higher degree, from the initial decision to the viva and beyond, and although it con. sists mostly of obvious statements, it is useful to have them gathered together in an accessibleformat. From the beginning, Robert Beynon admits that life as a research student is far from a bed of roses; the book starts off with a depressingly realistic list of the negative aspects of a career in research. However, the reader who manages to make it past the first paragraph will be rewarded for his/her persistence. Working relationships are first on the menu, with the emphasis on the student-supervisor relationship (most supervisors would do well to read this - it takes two to tango). The next chapter, on development of experimental skills, contains an excellent section on design of properly controlled experiments, offers advice on dealing with equipment (try reading the manual, for example - if you can find it!), and explains the importance of being objective. The chapter on conducting a research project is probably the most valuable. It contains many of the truths that students usually know but choose to ignore, such as the facts that preparing posters,
reports and theses takes a finite amount of time, that it is never possible to record too m.,Jch in a labora. tory notebook, and that it really is necessary to keep up with the literature on a regular basis. Together with subsequent chapters on scientific writing, giving talks, and teaching under. graduates, this chapter really brings it home that there is much more to doing a PhD than slaving away at the lab bench. The thing I like most about this book is the author's balanced approach: he does not pretend that things wiU always run smoothly, but he is also not unduly pessimistic. He describes likely situations and also offers very sensible guidelines for making the best of a 'worst.case scenario'. When I had finished reading the book, I was left with the feeling that I would like to go back and do my PhD again, only properly. My main concern, however, is that if I had really designed each experiment carefully, read the manual for each piece of equipment I used, written up every experiment properly, gone to the library every week and recorded every interesting paper in a computerized bibliography, I might still be there in another three years' time.
References 1 CellBiologyoftheExtracellularMatrix(2nd edn)(1991)(Hay,E.D., ed.), Plenum Press 2 CURRAN,M. F., ATKINSON,D. L., EWART,A. K., MORRIS,C. A., LEPPERT, M. F.and KEATING,M. T. (1993)Ce//73, 159-168 3 BENTZ,H., MORRIS,N. P., MURRAY,L., SAKAI,L. Y., HOLLISTER,D.W. and BURGESON,R. E.(1983)Proc.NotlAcad. Sci. USA80, 3168-3172 4 CHRISTIANO,A. M. et ol. (1993)Nature Genet.4, 62-66 S SAKAI,L Y., KEENE,D. R. and ENGVALL, E. F. (1986)I. CellBiol. 103, 2499-2509 6 DIETZ,H. C. etoL (1991)Nature 352, 337-339 7 VASSAR,R.,COULOMBE,P.A., DEGENSTEIN,L., ALBERS,K. and FUCH,E.(1991)Cell64, 365-380
TRENDS IN CELLBIOLOGYVOL. 3 OCTOBER1993
been made to emphasize details that are known to be critical for successful reconstitution, but that are often either not included or not obvious in the original published methods. My major criticism of these chapters is that they could benefit from more uniform use of simple diagrams to illustrate the system and its component parts, as well as diagrams for some of the techniques. The final section of this volume, 'Identification of transport intermediates', could be more readily called 'Purification and characterization of transport proteins'. Although four chapters describe methods for the isolation of transport vesicles and manipulations that can be used to define sequential intermediates in transport, the majority of the chapters present
The ECM: structure, function and dysfunction Connective Tissue and Its Heritable Disorders: Molecular, Genetic and Medical Aspects edited by PeterM. Royceand Beat Steinmann, Wiley.Liss, 1992. £185.00 (724 pages) ISBN471 588 199 In the last ten years, there has been enormous progress in our understanding of the extracellular matrix. The point that collagen is more than just 'glue' has been driven home many times. We now know that collagen comes in many types (types VI-XVII ha~e been characterized in the last decade), which have different tissue distributions and different fine structures. We have also learned that mutations in different collagen genes lead to different heritable disorders of connective tissue. And, significant progress has been made in identifying, characterizing and sequencing more than 25 additional noncollagenous inhabitants of the extracellular matrix. There have been reviews of many of these extracellular matrix compo-
methods for purifying and characterizing endogenous and recombinant transport-t'elated proteins. Unlike the earlier chapters, many of these protocols do not seem to contain significantly more information than is found in the original published methods. This section does, however, contain the only published protocol for purifying recombinant NSF, and a useful compendium of the seemingly limitless family of rab proteins. In summary, this volume is an excellent guide to the available systems for reconstitution of transport within the vacuolar system, both in yeast and mammalian cells, and to the transport-related proteins that have been identified to date. On the other hand, it does not really provide a coherent framework of
general considerations and methodology applicable to the design of such systems from scratch. What then is the purpose of this collection? I would like to think that it is more than just a monument to the ingenuity and skills of the scientists who developed these in vitro systems. Perhaps it is a sign that in vitro reconstitution of transport is 'coming of age' - making the transition from being a novelty to a tool available to all cell biologists, whether they are pioneers or not. This volume constitutes the first step in making this technology accessible. One hopes that this will lead to a second wave of innovation, as more energy is focused on the different aspects of transport that are amenable to dissection with these characterized systems.
nents and of connective tissues like skin and cartilage, and an excellent book on the cell biology of the extracellular matrix has been recently updated 1. Connective Tissue and Its Heritable Disorders is a kind of compendium, intended to 'be of benefit not only to clinical and associated personnel, but also to basic scientists for whom the juxtaposition of basic and clinical reviews within one set of covers might aid an enhanced awareness of the functional significance of the molecules they are studying.' The concept of heritable disorders of connective tissue was originally developed by Victor MCKusick (whose last edition of Heritable Disorders of Connective Tissue appeared 20 years ago) in relation to the Marfan syndrome, and then extended to include osteogenisis imperfecta (OI), the Ehlers-Danlos syndrome (EDS), pseudoxanthoma elasticum, cutis laxa, the mucopolysaccharidoses, the chondro.. dysplasias, fibrodysplasia ossificans progressiva, and disorders like homocystinuria, alkaptonuria and Menkes syndrome, which can secondarily affect the connective tissue. The latter half of Connective Tissue and Its Heritable Disorders contains chapters on each of these classical disorders. The molecular bases of Marfan syndrome, OI, some subtypes of EDS and some chondrodysplasias have now been identified and are well reviewed in this book. These include molecular abnormalities in
type I, II and III collagens and in more recently characterized extracellular matrix molecules. In addition, the editors have included chapters on epidermolysis bullosa, disorders of keratinization, prolidase deficiency, (xl-antitrypsin deficiency, osteopetrosis and heritable rickets. The first half of the text is composed of chapters on the biology of the extracellular matrix, including reviews of connective tissue morphology (skin and tendon, cartilage and bone), molecules (collagens, elastin, glycosylated matrix proteins, adhesive glycoproteins and keratins), bone biology and extracellular matrix degradation. Each of these chapters collates current information in a readable fashion. The heritable disorders of connective tissues were first classified as such by their visible dramatic effects upon tissues like skin (soft and rubbery in EDS; loose in curls laxa) and bone (brittle and easily broken in OI; excessively long in the Marfan syndrome; short in the chondrodysplaslas), which contain large amounts of ECM. Nowadays, with increased knowledge o| the molecular components of the ECM, the classification of heritable disorders of connective tissue will be continually expanded _~s molecular defects in these components are discovered in genetic diseases. For example, MCKusick suggests in his introduction that Stickler syndrome and Alport syndrome might warrant separate chapters, since these
TRENDS IN CELL BIOLOGY VOL. 3 OCTOBER 1993
Peggy Wiedman Saint Louis University Medical Center, 1402 South Grand Boulevard, St Louis, MO 63104, USA.
361
MISCELLANEA
Lynn Y. Sakai ShrinersHospital for Crippled Children, Departmentof Biochemist~ and Molecular Biology, Oregon Health Sciences University, Portland, OR, USA.
syndromes are associated with defects in type II collagen (Stickler) and type IV collagen (Alport). The recent discovery of a translocation disruption of the elastin gene in families with the inherited disease supravalvular aortic stenosisz might now also qualify this disorder for an individual chapter. Moreover, as additional components of the extracellular matrix are discovered and characterized, new candidate genes for inherited diseases will become available. This has been demonstrated recently in the cases of type VII collagen3 and epidermolysis bullosa dystrophica"~, and fibrillin s and the Marfan syndrome6. This book is both a timely and a comprehensive resource. It communicates the growing complexity of the extracellular matrix and the expansion of knowledge of the heritable disorders of connective tissue. Progress on heritable disorders has been driven by the integration of developments in basic research with clinical investigations, and this is reflected here in the inclusion of reviews on both basic research and clinical aspects.
Curing the PhD blues Postgraduate Study in the Biological Sciences: A Researcher's Companion
Catherine Brookshank Trends in Biochemical Sciences
362
by Robert J. Beynon, Portland Press, 1993. £9.50 (xi + 151 pages) aSBN 1 85578 009 7
This little book is a rnust for anyone starting out on a career in research. Its nine sympathetically written chapters offer sound advice on every
It is appropriate that Royce and Steinmann offer this book as an aid to 'enhanced awareness' by research scientists of the functional significance of the molecules they study. Scientists interested in bone, for example, might also read about fibrodysplasia ossificans progressiva and come up with interesting ideas regarding its etiology. These days, however, it is equally likely that scientists interested in particular components will employ every available technology to determine the functional significance of their molecules, and these technologies may themselves generate the hypotheses relevant to human disease. We have already seen the utility of this approach in, for example, the comparison of the effects of engineered mutant keratin with epidermolysis bullosa simplexz. Similar functional studies are underway for most of the extracellular matrix molecules reviewed in this book. For some of these molecules, engineered mutations may result in phenotypes resembling the classical heritable disorders of connective tissue or other inherited diseases that could
become classified as such. My only criticism of the book is that, for basic scientists interested in the exploitation of new technologies to study function, there is little emphasis placed on the available examples and the potential of these technologies for contributing to the under. standing of human disease.
aspect of doing a higher degree, from the initial decision to the viva and beyond, and although it con. sists mostly of obvious statements, it is useful to have them gathered together in an accessibleformat. From the beginning, Robert Beynon admits that life as a research student is far from a bed of roses; the book starts off with a depressingly realistic list of the negative aspects of a career in research. However, the reader who manages to make it past the first paragraph will be rewarded for his/her persistence. Working relationships are first on the menu, with the emphasis on the student-supervisor relationship (most supervisors would do well to read this - it takes two to tango). The next chapter, on development of experimental skills, contains an excellent section on design of properly controlled experiments, offers advice on dealing with equipment (try reading the manual, for example - if you can find it!), and explains the importance of being objective. The chapter on conducting a research project is probably the most valuable. It contains many of the truths that students usually know but choose to ignore, such as the facts that preparing posters,
reports and theses takes a finite amount of time, that it is never possible to record too m.,Jch in a labora. tory notebook, and that it really is necessary to keep up with the literature on a regular basis. Together with subsequent chapters on scientific writing, giving talks, and teaching under. graduates, this chapter really brings it home that there is much more to doing a PhD than slaving away at the lab bench. The thing I like most about this book is the author's balanced approach: he does not pretend that things wiU always run smoothly, but he is also not unduly pessimistic. He describes likely situations and also offers very sensible guidelines for making the best of a 'worst.case scenario'. When I had finished reading the book, I was left with the feeling that I would like to go back and do my PhD again, only properly. My main concern, however, is that if I had really designed each experiment carefully, read the manual for each piece of equipment I used, written up every experiment properly, gone to the library every week and recorded every interesting paper in a computerized bibliography, I might still be there in another three years' time.
References 1 CellBiologyoftheExtracellularMatrix(2nd edn)(1991)(Hay,E.D., ed.), Plenum Press 2 CURRAN,M. F., ATKINSON,D. L., EWART,A. K., MORRIS,C. A., LEPPERT, M. F.and KEATING,M. T. (1993)Ce//73, 159-168 3 BENTZ,H., MORRIS,N. P., MURRAY,L., SAKAI,L. Y., HOLLISTER,D.W. and BURGESON,R. E.(1983)Proc.NotlAcad. Sci. USA80, 3168-3172 4 CHRISTIANO,A. M. et ol. (1993)Nature Genet.4, 62-66 S SAKAI,L Y., KEENE,D. R. and ENGVALL, E. F. (1986)I. CellBiol. 103, 2499-2509 6 DIETZ,H. C. etoL (1991)Nature 352, 337-339 7 VASSAR,R.,COULOMBE,P.A., DEGENSTEIN,L., ALBERS,K. and FUCH,E.(1991)Cell64, 365-380
TRENDS IN CELLBIOLOGYVOL. 3 OCTOBER1993