Genes & Signals

Rating:
Summary: Executing the programs of life
Review: This is a great book on the mechanisms of cellular regulation. It will give the "Intelligent Design" types a heart attack, but it should be read by anybody who is interested in how living things work. This book does the impossible: it is clear enough to serve the need of people in other fields and it goes into enough detail (especially in the notes) to serve as a guide to the research literature.

The first chapter discusses gene regulation in bacteria. Of the mechanisms identified for regulation, the most common by far is recruitment. Recruitment means simply that the gene activator operates by making the attachment of the RNA polymerase enzyme to the gene promoter more probable. This is a very inelegant mechanism.

It is not completely true that gene regulation is always digital: in the case of the lac gene, in the absence of the CAP activator, gene transcription still happens at a reduced rate, due to random attachment of the RNA polymerase to the promoter. The CAP activator increases the transcription rate by a factor of about forty.

More digital is the example of the lambda switch, where the lambda repressor, while suppressing the transcription of the cro gene, actually activates its own production (up to a point, otherwise there would be an exponential growth of the lambda repressor.) On the other hand, the cro gene product represses production of its own repressor. The system works like a flip-flop.

The lambda repressor is an example of a protein that binds cooperatively to DNA. Cooperative binding, when different proteins are involved, allows combinatorial control of gene expression and is a recurrent theme of the book.

Chapter 2 discusses a simple eukaryotic cell: yeast. Eukaryotic cells are much more complicated in part because of the fact that the DNA is wrapped around proteins called histones, to form nucleosomes. However, when nucleosome modifiers are needed for gene control, the activators that recruit the RNA polymerase enzyme also recruit the nucleosome modifiers. The same principles operating in bacteria are also operating, but with much greater complexity. Cooperative binding, combinatorial control and signal integration still work essentially in that same way as in the bacteria.

This is a strong argument in favor of evolution and against design, because evolution by tinkering is expected to produce more and more complex systems when higher accuracy is needed, rather than switching to new, more elegant schemes, as design would predict.

Chapter 3 discusses higher Eukariotes (like humans). The mechanisms of regulations are still the same, but there is more of them, more signal integration, more combinatorial control, etc. the Human interferon-beta gene is switched on by three activators working together, but the mechanisms are still cooperative binding and enzyme recruitment.

Chapter 4 discusses the regulation of enzymatic functions. It is again shown that regulation is still mostly the result of recruitment. Discussed is the control of proteolysis and of splicing of introns from mRNA. Recruitment is still the most common mechanism. Also discussed is binding of signaling proteins to cell-surface receptors.

Because recruitment is such an important mechanism, it would be nice to have a better discussion of the thermodynamic nature of the process. Appendix 1 does explain that, because of the exponential dependence of the dissociation constant on the binding energy, a few kilocalories of binding energy between cooperatively binding proteins can have a very dramatic effect on site occupancy.

Since I have discussed how this book supports standard evolutionary ideas against Intelligent Design, I should also point out that the author does deviate from orthodox neo-Darwinism in that he seems to agree with Francois Jacob and others in postulating that macroevolution and especially the Cambrian explosion of animal body-plans was caused mostly by changes in regulatory genes. This idea is now entering the mainstream: I am pretty sure that the high-priests of Darwinism will soon proclaim that the idea was always part of orthodox Darwinism, despite all the historical evidence to the contrary.



Rating:
Summary: Transcription at its best!
Review: Transcription is digital. It was the concept first introduced by François Jacob, André Lwoff and Jacques Monod that won them the Nobel Prize in Physiology or Medicine in 1965. Switching between ON/OFF states, cells are constantly faced with a decision-making process (to transcibe or not?) that contributes to its fate- be it differentiation (as in development), survival or suicide (as in programmed cell death).
Mark Ptashne is one of the leading gurus in this area of research, especially in the area of transcriptional regulation in prokaryotes (author of the Genetic Switch). In this book, Ptashne and Gann emphasize on how cells execute this elaborate process. Signaling specificity is the major focus in this area of research. How does a cell know when to transcribe a particular gene in response to a signal (extracellular or intracellular)? Put differently, how does the same signal upstream result in a different output (transcription of a particular gene) at any given time? The authors provide answers to such questions and take it a step further by discussing the plasticity or 'evolvability' in transcription.
The book is beautifully organized with four chapters (forward by Tony Pawson), from transcription in prokaryotes and lower eukaryotes to metazoans that allows the reader to appreciate the evolutionarily conserved biochemistry behind the process. They drive home the idea of regulated recruitment at the proximal and distal promoter regions of the gene- protein-protein interactions (by cooperrativity and allostery) on DNA involve low affinity interactions, that help increase local concentrations of transcription factors at cis-acting regions. The conclusions are simple and very elegant. The book features excellent illustrations without too many details that one normally encounters with gene structures. The reader is referred to papers and articles that are all categorized under subtitles that complement the text. On-line material at genesandsignals.org provides references that link to Pubmed. The website also features four lectures (one on each chapter) delivered by Ptashne at Rockefeller University. The parts of the book that I most liked were the footnotes. The footnotes in each chapter takes the reader to more details on ongoing research. The entire book is meant to be read beginning from the first chapter. I thoroughly recommend this book that should be used for graduate course work. As a graduate student myself, I found this book extremely helpful and a valuable reference. A definite must-read!

Rating:
Summary: Transcription at its best!
Review: Transcription is digital. It was the concept first introduced by François Jacob, André Lwoff and Jacques Monod that won them the Nobel Prize in Physiology or Medicine in 1965. Switching between ON/OFF states, cells are constantly faced with a decision-making process (to transcibe or not?) that contributes to its fate- be it differentiation (as in development), survival or suicide (as in programmed cell death).
Mark Ptashne is one of the leading gurus in this area of research, especially in the area of transcriptional regulation in prokaryotes (author of the Genetic Switch). In this book, Ptashne and Gann emphasize on how cells execute this elaborate process. Signaling specificity is the major focus in this area of research. How does a cell know when to transcribe a particular gene in response to a signal (extracellular or intracellular)? Put differently, how does the same signal upstream result in a different output (transcription of a particular gene) at any given time? The authors provide answers to such questions and take it a step further by discussing the plasticity or `evolvability' in transcription.
The book is beautifully organized with four chapters (forward by Tony Pawson), from transcription in prokaryotes and lower eukaryotes to metazoans that allows the reader to appreciate the evolutionarily conserved biochemistry behind the process. They drive home the idea of regulated recruitment at the proximal and distal promoter regions of the gene- protein-protein interactions (by cooperrativity and allostery) on DNA involve low affinity interactions, that help increase local concentrations of transcription factors at cis-acting regions. The conclusions are simple and very elegant. The book features excellent illustrations without too many details that one normally encounters with gene structures. The reader is referred to papers and articles that are all categorized under subtitles that complement the text. On-line material at genesandsignals.org provides references that link to Pubmed. The website also features four lectures (one on each chapter) delivered by Ptashne at Rockefeller University. The parts of the book that I most liked were the footnotes. The footnotes in each chapter takes the reader to more details on ongoing research. The entire book is meant to be read beginning from the first chapter. I thoroughly recommend this book that should be used for graduate course work. As a graduate student myself, I found this book extremely helpful and a valuable reference. A definite must-read!