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Accelerated evolution
Cell, Vol. 43, 391-392,
December
1985 (Part
l), Copyright
0 1985 by MIT
Book Reviews
First Insulin Binds . . . and Then Something Happens Molecular Basis of Insulin Action. Edited by M. F? Czech. New York: Plenum Press. (1985). 473 pp. $59.50.
Those present at the bedside of Leonard Thompson, who was so dramatically treated with some of the first therapeutically useful insulin preparations, would have been understandably optimistic that the rapid conquest of diabetes was at hand and that the mechanism of insulin action would soon be completely understood. However, as Molecular Basis of Insulin Action, edited by Czech, clearly indicates-here we are over sixty years since the discovery of insulin and we are still unable to describe with precision exactly how this molecule works. It is now well recognized that insulin first binds to its receptor, thereby setting in motion a series of receptor-mediated processes that result in target cell activation. But so many things can happen in so many different cell types in response to insulin (ranging from an increase in glucose transport to the stimulation of cell division), that it has been difficult to determine which, if any, of the receptor-mediated reactions represents the “primary” membrane signal that leads to all responses in all cells. Like King Savatthi’s blind men from beyond Ghor describing the elephant, the sixty-eight contributors to this twenty-six chapter volume all view insulin action from quite varied perspectives. It is interesting that the insulin receptor per se (isolation, subunit structure, metabolism), which has formed such an intense focal point for those working on the mechanism of insulin action over the past decade, commands a comparatively small proportion (about 20%) of the text. Commendably this erudite, if not eclectic, collection of multiauthored articles directs attention to a wide variety of reactions triggered by insulinreactions involving the cell membrane (two chapters on membrane potential; three chapters on hexose transport; one chapter on [Na+, K+]-ATPase), cellular enzymes (three chapters on glycogen synthase; two chapters on acetyl CoA carboxylase), and the nucleus (four chapters on the regulation of nuclear functions and gene expression). Appropriately, a significant amount of attention is drawn to the notion that phosphorylation-dephosphorylation reactions may play a central role in the action of insulin. The tyrosine kinase activity of the receptor itself is dealt with in some detail, as is the role of phosphorylation in the context of glycogen synthase and acetyl CoA carboxylase control. Other key cell messages received subsequent to insulin binding are also described. These include changes in membrane potential (two chapters), changes in cellular calcium (one chapter), and the generation of the still elusive low-molecular-weight mediators of insulin action (three chapters).
No doubt there will be some readers who will be disappointed that their preferred mechanism for insulin action (such as the generation of peroxide or the modulation of a guanine nucleotide regulatory protein) is not to be found in this volume; and there may be others who will wish that the book had been delayed long enough so as to contain the gene sequence data now available for the receptor. On the whole, however, those who have contributed to the volume are to be congratulated along with the editor for having provided a timely, authoritative, and comparatively comprehensive view of the molecular aspects of insulin action. Molecular Basis of Insulin Action will appeal largely to those heavily involved in unraveling the mechanisms of hormone action and to those working on the actions of growth factors and oncogene products related to insulin and its receptor. It may be less useful, except perhaps as an encyclopaedic reference source, for those who are slightly removed from the laboratory bench and who may have difficulty sifting through its wealth of details. It is left to the Flexnerian perspective of the reader to see how the basic information described in the text relates to the problem of diabetes and other areas of pathophysiology, including cancer. In terms of the mechanism of resistance to insulin that characterizes type II diabetes, this volume offers much hope and represents a significant landmark along the way to an understanding. As yet, however, when the “real insulin message” is asked to stand up, all appear reluctant to rise. Perhaps the main message of this book is that the cellular signals generated in response to insulin are multiple. Morley D. Hollenberg Endocrine Research Group Department of Pharmacology and Therapeutics University of Calgary, Faculty of Medicine Calgary, Alberta, Canada T2N 4Nl
Accelerated Evolution Microorganisms as Model Systems for Studying Evolution. Edited by Ft. P. Mortlock. New York: Plenum Press. (1984). 328 pp. $49.50.
For many years, some population biologists have appreciated that microbial systems might constitute the optimal material for the experimental investigation of evolution. Large numbers of individuals can be grown rapidly, and selection can be imposed under rigorously controlled conditions. What more could an evolutionist want? Throughout its history, evolutionary science seems to
Cell 392
have experienced as much difficulty in defining the important questions as in answering them. Often the apparent choice is either to ask rather intractable general questions (such as whether most natural variation is neutral or selected) or to limit oneself to problems so specific that the results seem anecdotal. Microbial evolutionists have not escaped this dilemma. Nevertheless, their studies have produced a body of knowledge of a type that would be difficult to match with higher organisms. In the ten independent chapters of Microorganisms as ModelSystems for Studying Evolution, edited by R. P Mortlock, nine authors describe experiments on microbial evolution. Most chapters summarize primarily work from the authors’ laboratories. One of the most fruitful approaches for studying microbial evolution has been to impose selective regimes that require microorganisms to evolve new metabolic functions. Such studies bypass all the neutral, perhaps evolutionarily irrelevant, genetic variation observable in populations and focus on the small minority of such variation that directly affects fitness. The clearest exposition of the advantages and achievements of this approach is presented by Barry Hall in his chapter on the evolved /?galactosidose of E. coli. Patricia Clarke provides extensive additional examples from her research on new amidase specificities in Pseudomonas. In both cases, the interplay between changes in structural and regulatory genes is instructive. The first five chapters of the volume include additional examples from pathways of pentitol and pentose metabolism in the Enterobacteriaceae. Perhaps the main lesson from all these studies is simply that profound changes in metabolic and regulatory specificity may require only a small number of mutations. The feeble but real activity of the typical enzyme on substrates other than its “natural” one (sometimes treated by enzymologists as accidental or even artifactual) can easily be improved by mutation, thus providing a basis for metabolic evolution and raising the question whether genes encoding enzymes with such flexibility may have been favored in organisms faced with variable environments. A poor natural activity on the selected substrate can be improved either by a mutation that alters enzyme specificity or by an increase in amount of enzyme through derepression or amplification. Regulatory specificity appears to be as malleable as structural specificity. Changes in regulatory specificity presumably result from alterations in the affinity of a regulatory protein for an inducer or a corepressor, although the direct biochemical evidence is limited. At any rate, it is clear that a fair facsimile (in terms of both structural and regulatory specificity) of the lac opefon, for instance, can be generated rather readily from other genes of E. coli. Furthermore, the examples of experimental evolution discussed allow some generalizations about the preferred pathways of change, such as the “principle of preadaptation” developed by Lin and Wu in Chapter 5, which states that a structural gene that has been freed from its normal regulatory control by one selective event may constitute a prime target for further selec-
tive changes in various directions. Even allowing for the fact that this volume and the relevant literature chronicle the successes of experimental evolution rather than the attempts that failed, the ease with which major changes can occur may surprise those who assume that the systems we find in nature represent refined products of millenia of selection. Given the observations, a logical followup question is whether natural systems in fact initially arose by the most rapid pathways of change observable in the laboratory or whether there are also slower pathways that ultimately yield a better product and prevail in the long run; i.e., whether the highest adaptive peak is generally obtained without traversing some rather deep valleys. The last three chapters of the book concern evolution by means other than change of specificity. Christopher Wills cites the multiplicity of variations in yeast alcohol dehydrogenase structure that affect enzyme kinetics (selected by ally1 alcohol resistance) as indirect evidence for the selectionist hypothesis; Jost Kemper interprets the genetic interaction between the IeuD and supQ genes of Salmonella typhimurium as an example of recruitment of a borrowed subunit into an enzyme; and Monica Riley summarizes the evidence for genetic rearrangements of all sizes in the natural evolution of enteric bacteria. In general, each contribution is narrowly focused on a specific system. Some chapters summarize a large body of completed or published work, whereas others read more like progress reports of recent fragmentary data. Occasional statements are confusing or disconcerting, such as the implication that phage Pl attaches to F pili (p, 48) or that a reverse repeat in the DNA sequence containing a promoter creates a requirement to melt hairpins before initiating transcription (p. 93). The choice of the material for a volume of this kind properly reflects the interests of the editor. For this reviewer’s interests, the scope and balance are not ideal. Acquisition of new metabolic functions is one aspect of microbial evolution amenable to experimentation, but by no means the only one. Investigations such as Selander’s of the genetic structure of natural bacterial populations, the use of molecular cladistics as a key to bacterial phylogeny, laboratory studies on the maintenance of plasmids, as well as many aspects of chromosomal evolution barely touched on in Riley’s excellent chapter, might have been covered in depth. Acritical summary of all the important work on microbial evolution remains to be written. In the meantime, Microorganisms as Model Systems for Studying Evolution presents a series of informative case studies in the development of new metabolic functions under artificial selection and some discussion of their implications. Allan Campbell Department of Biological Sciences Stanford University Stanford, California 94305
December
1985 (Part
l), Copyright
0 1985 by MIT
Book Reviews
First Insulin Binds . . . and Then Something Happens Molecular Basis of Insulin Action. Edited by M. F? Czech. New York: Plenum Press. (1985). 473 pp. $59.50.
Those present at the bedside of Leonard Thompson, who was so dramatically treated with some of the first therapeutically useful insulin preparations, would have been understandably optimistic that the rapid conquest of diabetes was at hand and that the mechanism of insulin action would soon be completely understood. However, as Molecular Basis of Insulin Action, edited by Czech, clearly indicates-here we are over sixty years since the discovery of insulin and we are still unable to describe with precision exactly how this molecule works. It is now well recognized that insulin first binds to its receptor, thereby setting in motion a series of receptor-mediated processes that result in target cell activation. But so many things can happen in so many different cell types in response to insulin (ranging from an increase in glucose transport to the stimulation of cell division), that it has been difficult to determine which, if any, of the receptor-mediated reactions represents the “primary” membrane signal that leads to all responses in all cells. Like King Savatthi’s blind men from beyond Ghor describing the elephant, the sixty-eight contributors to this twenty-six chapter volume all view insulin action from quite varied perspectives. It is interesting that the insulin receptor per se (isolation, subunit structure, metabolism), which has formed such an intense focal point for those working on the mechanism of insulin action over the past decade, commands a comparatively small proportion (about 20%) of the text. Commendably this erudite, if not eclectic, collection of multiauthored articles directs attention to a wide variety of reactions triggered by insulinreactions involving the cell membrane (two chapters on membrane potential; three chapters on hexose transport; one chapter on [Na+, K+]-ATPase), cellular enzymes (three chapters on glycogen synthase; two chapters on acetyl CoA carboxylase), and the nucleus (four chapters on the regulation of nuclear functions and gene expression). Appropriately, a significant amount of attention is drawn to the notion that phosphorylation-dephosphorylation reactions may play a central role in the action of insulin. The tyrosine kinase activity of the receptor itself is dealt with in some detail, as is the role of phosphorylation in the context of glycogen synthase and acetyl CoA carboxylase control. Other key cell messages received subsequent to insulin binding are also described. These include changes in membrane potential (two chapters), changes in cellular calcium (one chapter), and the generation of the still elusive low-molecular-weight mediators of insulin action (three chapters).
No doubt there will be some readers who will be disappointed that their preferred mechanism for insulin action (such as the generation of peroxide or the modulation of a guanine nucleotide regulatory protein) is not to be found in this volume; and there may be others who will wish that the book had been delayed long enough so as to contain the gene sequence data now available for the receptor. On the whole, however, those who have contributed to the volume are to be congratulated along with the editor for having provided a timely, authoritative, and comparatively comprehensive view of the molecular aspects of insulin action. Molecular Basis of Insulin Action will appeal largely to those heavily involved in unraveling the mechanisms of hormone action and to those working on the actions of growth factors and oncogene products related to insulin and its receptor. It may be less useful, except perhaps as an encyclopaedic reference source, for those who are slightly removed from the laboratory bench and who may have difficulty sifting through its wealth of details. It is left to the Flexnerian perspective of the reader to see how the basic information described in the text relates to the problem of diabetes and other areas of pathophysiology, including cancer. In terms of the mechanism of resistance to insulin that characterizes type II diabetes, this volume offers much hope and represents a significant landmark along the way to an understanding. As yet, however, when the “real insulin message” is asked to stand up, all appear reluctant to rise. Perhaps the main message of this book is that the cellular signals generated in response to insulin are multiple. Morley D. Hollenberg Endocrine Research Group Department of Pharmacology and Therapeutics University of Calgary, Faculty of Medicine Calgary, Alberta, Canada T2N 4Nl
Accelerated Evolution Microorganisms as Model Systems for Studying Evolution. Edited by Ft. P. Mortlock. New York: Plenum Press. (1984). 328 pp. $49.50.
For many years, some population biologists have appreciated that microbial systems might constitute the optimal material for the experimental investigation of evolution. Large numbers of individuals can be grown rapidly, and selection can be imposed under rigorously controlled conditions. What more could an evolutionist want? Throughout its history, evolutionary science seems to
Cell 392
have experienced as much difficulty in defining the important questions as in answering them. Often the apparent choice is either to ask rather intractable general questions (such as whether most natural variation is neutral or selected) or to limit oneself to problems so specific that the results seem anecdotal. Microbial evolutionists have not escaped this dilemma. Nevertheless, their studies have produced a body of knowledge of a type that would be difficult to match with higher organisms. In the ten independent chapters of Microorganisms as ModelSystems for Studying Evolution, edited by R. P Mortlock, nine authors describe experiments on microbial evolution. Most chapters summarize primarily work from the authors’ laboratories. One of the most fruitful approaches for studying microbial evolution has been to impose selective regimes that require microorganisms to evolve new metabolic functions. Such studies bypass all the neutral, perhaps evolutionarily irrelevant, genetic variation observable in populations and focus on the small minority of such variation that directly affects fitness. The clearest exposition of the advantages and achievements of this approach is presented by Barry Hall in his chapter on the evolved /?galactosidose of E. coli. Patricia Clarke provides extensive additional examples from her research on new amidase specificities in Pseudomonas. In both cases, the interplay between changes in structural and regulatory genes is instructive. The first five chapters of the volume include additional examples from pathways of pentitol and pentose metabolism in the Enterobacteriaceae. Perhaps the main lesson from all these studies is simply that profound changes in metabolic and regulatory specificity may require only a small number of mutations. The feeble but real activity of the typical enzyme on substrates other than its “natural” one (sometimes treated by enzymologists as accidental or even artifactual) can easily be improved by mutation, thus providing a basis for metabolic evolution and raising the question whether genes encoding enzymes with such flexibility may have been favored in organisms faced with variable environments. A poor natural activity on the selected substrate can be improved either by a mutation that alters enzyme specificity or by an increase in amount of enzyme through derepression or amplification. Regulatory specificity appears to be as malleable as structural specificity. Changes in regulatory specificity presumably result from alterations in the affinity of a regulatory protein for an inducer or a corepressor, although the direct biochemical evidence is limited. At any rate, it is clear that a fair facsimile (in terms of both structural and regulatory specificity) of the lac opefon, for instance, can be generated rather readily from other genes of E. coli. Furthermore, the examples of experimental evolution discussed allow some generalizations about the preferred pathways of change, such as the “principle of preadaptation” developed by Lin and Wu in Chapter 5, which states that a structural gene that has been freed from its normal regulatory control by one selective event may constitute a prime target for further selec-
tive changes in various directions. Even allowing for the fact that this volume and the relevant literature chronicle the successes of experimental evolution rather than the attempts that failed, the ease with which major changes can occur may surprise those who assume that the systems we find in nature represent refined products of millenia of selection. Given the observations, a logical followup question is whether natural systems in fact initially arose by the most rapid pathways of change observable in the laboratory or whether there are also slower pathways that ultimately yield a better product and prevail in the long run; i.e., whether the highest adaptive peak is generally obtained without traversing some rather deep valleys. The last three chapters of the book concern evolution by means other than change of specificity. Christopher Wills cites the multiplicity of variations in yeast alcohol dehydrogenase structure that affect enzyme kinetics (selected by ally1 alcohol resistance) as indirect evidence for the selectionist hypothesis; Jost Kemper interprets the genetic interaction between the IeuD and supQ genes of Salmonella typhimurium as an example of recruitment of a borrowed subunit into an enzyme; and Monica Riley summarizes the evidence for genetic rearrangements of all sizes in the natural evolution of enteric bacteria. In general, each contribution is narrowly focused on a specific system. Some chapters summarize a large body of completed or published work, whereas others read more like progress reports of recent fragmentary data. Occasional statements are confusing or disconcerting, such as the implication that phage Pl attaches to F pili (p, 48) or that a reverse repeat in the DNA sequence containing a promoter creates a requirement to melt hairpins before initiating transcription (p. 93). The choice of the material for a volume of this kind properly reflects the interests of the editor. For this reviewer’s interests, the scope and balance are not ideal. Acquisition of new metabolic functions is one aspect of microbial evolution amenable to experimentation, but by no means the only one. Investigations such as Selander’s of the genetic structure of natural bacterial populations, the use of molecular cladistics as a key to bacterial phylogeny, laboratory studies on the maintenance of plasmids, as well as many aspects of chromosomal evolution barely touched on in Riley’s excellent chapter, might have been covered in depth. Acritical summary of all the important work on microbial evolution remains to be written. In the meantime, Microorganisms as Model Systems for Studying Evolution presents a series of informative case studies in the development of new metabolic functions under artificial selection and some discussion of their implications. Allan Campbell Department of Biological Sciences Stanford University Stanford, California 94305