An unabridged view of the TGF-β family

Which came first within the Transforming growth factor β (TGF-β)superfamily, the TGF-β subfamily or the BMP subfamily? Of course, the answer depends upon how one defines `first': is it the first to come to the attention of researchers or the first to exist on the planet? The answer to the first version of this question can be found in The TGF-β Family, the new monograph from Cold Spring Harbor Laboratory Press that covers the TGF-β superfamily. For the answer to the second, one must read on.FIG1 

In this review, I intend to do four things. First, I will try to put this book into perspective. Second, I'll share a few basic facts. Third, I'll give my impressions of the book's strengths and weaknesses and fourth, I'll provide my view as to who will be well served by keeping a copy of this book handy.

For perspective, take a moment to recall where you were in 1978 when the first partial purification of what would become known as TGF-β1 was reported. I was an undergraduate at that time and did not publish my first TGF-β paper until many years later, in 1994. Now, take into consideration the fact that a search of PubMed with the word `TGF-beta' returned 39,641 entries in September 2008 (by comparison, the search term `Wnt' returned 7496 entries). To date, a comprehensive review of the TGF-β field has been lacking and thus the book fills an important niche.

Next, a few basic facts. The 1114-page book begins with a Preface by the editors Rik Derynck and Kohei Miyazono, a Forward by Michael Sporn and two introductory chapters. The first of these chapters is written by Harold Moses and Anita Roberts, who provide a personal view of the context surrounding the discovery of TGF-β. The other introductory chapter is an overview of the field by the editors. These are followed by 31 chapters devoted to distinct topics of TGF-β research: three chapters of cell biology; ten chapters of signaling; 12 chapters of differentiation, development and physiology; and six chapters of cancer and disease.

One measure of the comprehensive nature of this book is the fact that 64 distinct authors representing seven countries contributed to its 33 chapters,with only three authors present on more than one chapter. Furthermore, authors appear to have been given full authority over their chapters, as many are lengthy: six are roughly 50 pages and several others are over 40 pages long. All chapters are accompanied by at least two illustrations. Frequently, these are nicely color-coded schematics or flow-charts representing `take-home messages' identified by the authors for that topic. A few chapters contain color figures of original data, although only one chapter includes original data that do not appear to have been published previously.

This celebration of the TGF-β field is not without its somber side. With sadness, I note the inclusion of chapters co-authored by Anita Roberts(the historical perspective, with Harold Moses) and Kai Lin (on receptor assembly and specificity, with Senyon Choe), both of whom passed away in 2006. A brief retrospective describing the contributions of these investigators is contained in the Preface, and Figure 3C from the chapter by Kai Lin graces the book's cover.

In reflecting on the book's strengths and weaknesses, in my view the strengths are many and profound and the weaknesses are few. Let me begin with the strengths. As clearly stated, the editors intended to be as comprehensive as possible and, although I have one quibble (discussed below), there is really little doubt that they have succeeded. The breadth and depth of the coverage of current TGF-β research is the most compelling feature of this book. To illustrate the depth of coverage, the chapter on TGF-β signaling in Drosophila by George Pyrowolakis, Britta Hartmann and Markus Affolter encompasses 34 pages with four color diagrams and lists roughly 150 citations. The authors clearly describe the basic components of fly TGF-βpathways, several mechanisms of transcriptional repression employed by BMP signal transducers and the salient features of BMP gradient formation in embryos versus wing primordia. The chapter neatly ends with a set of currently unanswered questions. Looking beyond individual chapters, the book's subject index helps the reader to navigate towards the most relevant chapter, and frequent cross-referencing between chapters aids in stitching them into a cohesive volume.

Given these strengths, it is my recommendation that every principal investigator studying TGF-β should have a copy of this book for the following reason. In a multi-faceted field such as TGF-β research, the learning curve is extraordinarily steep for newcomers, such as graduate students, newly minted post-docs and even experienced PIs, who find themselves following their research program into the TGF-β world. Until now, those of us running TGF-β labs would spend a considerable amount of time guiding these newcomers as they compiled their library of relevant papers and in subsequent discussions of those papers, as they pieced together for themselves the current working hypotheses in the field. Now, this task is likely to be much easier as newcomers can begin independently by reading the most relevant chapters and making sense of the big picture, as sketched out by the authors. Once this framework is in place, current reviews in the primary literature can be digested more easily. For example, the chapter on growth control by TGF-β (Peter Siegal and Joan Massagué) can be followed up with a recent review on TGF-β in cancer(Massagué, 2008). Thus,the process of `getting up to speed' becomes far less arduous.

The books strengths are also relevant to those of us who teach. Instructors in graduate specialty courses are often at their wits end in finding suitable materials above the textbook level (which the students should already know)but a bit below the primary literature (which can be too detailed, at least at the beginning for first year students). For the next few years, I believe this book will effectively fill that gap. At 40-50 pages, each chapter contains far more detail than any textbook, yet, in synthesizing existing knowledge, the authors inevitably weed out distracting details and conclude with an excellent summary that leads directly to the primary literature. Furthermore, the book's structure of 33 individual chapters is a nearly perfect fit to a course that meets once or twice a week for a semester. I recommend that faculty members teaching graduate courses in any discipline employed in TGF-β research(biochemistry, cell biology, development, genetics and oncology, to name just a few) consider adding this book to their syllabus.

Of the few weaknesses I noted, one is perhaps unavoidable in a work of this magnitude and another is likely to be beyond editorial control. First, the process of gathering, editing, proofreading and typesetting 33 distinct chapters is inherently time-consuming. As a result, the newest papers cited in the book are from 2006 and, in several chapters, from 2005. Second, in late 2004, many of the most prominent investigators were invited to contribute chapters to two books - this one and Smad Signal Transduction, edited by Peter ten Djike and Carl-Henrik Heldin and published by Springer (ably reviewed in these pages last year). The more focused (22 chapters) and strongly edited Smad book (in which the chapters were limited to 20 pages) was published in 2006. Of those invited to write for both books, many wrote chapters on distinct topics and these individuals should be applauded. Others wrote chapters on the same topic but presented the information in a new way. There were several authors who chose only to make minor changes. The latter might not have been visible to the editors of The TGF-β Family as both books were being compiled simultaneously.

Now it is time to return to my quibble and this also leads back to the opening question. In my view, an area of active TGF-β research absent from the book is computational biology. Here, I use this term to encompass a wide array of non-experimental approaches that include phylogenetics, kinetic and Boolean modeling, interactome construction and comparative genomics. Thus,I provide the answer to the second version of the opening question: the best evidence to date, from two species of sponge, suggests that the BMP subfamily pre-dated the TGF-β subfamily. Computational research is emerging as one of the hottest areas in the TGF-β field. This is particularly true in Europe, where strong sponsorship is provided by ENFIN, the European Network of Excellence in Data Integration and Systems Biology. In hindsight, it is true that four years ago when chapters for The TGF-β Familywere being solicited, this area of research was far smaller than it is now.

In summary, I rank The TGF-β Family among the handful of books such as the `Red Book' for fly geneticists or `Maniatis' for molecular biologists that in their time provided definitive guidance for researchers. This book belongs in every TGF-β lab.