Applications of Network Thermodynamics to Problems in biomedical Engineering
Preface and Acknowledgments:
This book is basically the result of nine years of teaching the material to physiology, pharmacy and biomedical engineering students. Some of the "students" have also been faculty and post-docs. I am very grateful to them for their patience and tolerance as it progressed from crude notes to its present form. The material owes its existence to many conversations and collaborations with Leonardo Peusner and many more hours of reading and rereading his work. Leonardo is one of the few people I've met who I'd consider a genius. Another is the late Aaron Katchalsky, who was my post-doctoral mentor and the real beginning of my education. I miss him very much. Bob Rosen has also been a big source of inspiration and ideas and a model for what a scholar in theoretical biology might be.
The topic of "network thermodynamics" has become more than a technical subject to me. When I first discovered the topic at the end of the 1960s, it seemed like the world had been waiting for this powerful approach to the hierarchical organization of living systems. I anticipated it sweeping the biomedical sciences, and foresaw a network/circuits type course becoming a part of the undergraduate curriculum serving a parallel foundation role to analogous courses in the curriculum in electrical engineering. I was very wrong! As one does when one misjudges a situation that greatly, I searched for an explanation. I now understand the situation quite to my own satisfaction, although the explanation is not reassuring.
The philosophical "mind-set" taught to biomedical scientists is very different from that underlying engineering education. The emphasis on "molecular biology" signals the strong reliance on reductionism in modern biomedical science. In contrast, engineers are usually concerned with synthesis and whole systems. As a teacher, I see the distinction in the different reactions of my students to the material, and more importantly, the approach. Hence this book seems very appropriately located in a series on biomedical engineering. There is no need to elaborate further on this theme here, since it has been woven into the fabric of the book. It has deeper implications for the future of biomedical science, for, sooner or later, the results of having broken down the living system to smaller and smaller parts will have lead to a mass of information waiting to be synthesized into models of the working whole. The subject matter of this book dwells on how that can be done. In some ways, philosophically, the term "molecular biology" is an oxymoron, to the extent that biology is the study of life. Without putting a lesser value on the marvelous results of molecular level studies, it is hard to see that anything resembling life exists at that level of organization. If this point is understood, a world of constructive engineering research lies in front of anyone willing to take it seriously. It is my belief that engineering has very much to contribute to basic theoretical biology. I hope enough students see this to make it happen. If this book contributes in any small way to that future progress, it will have served its purpose.
The material in the book is written for persons at a number of levels. Much of it is introductory for an engineer, but serves to link engineering principles with living systems by analogy. For that reason, it needs to be studied with some care. To the average biomedical scientist, much of it will be tough going, but, hopefully, rewarding if mastered. Fortunately, much of the application has been made by clinicians who were not special in their quantitative training. The simulation program SPICE allowed them to see these complicated mathematical problems pictorially and allowed for a simpler, more direct formulation of the simulations than in methods requiring the explicit writing of equations. I use it as the text for a one semester advanced graduate course for a very mixed audience. The course consists of three hours lecture per week plus a computer simulation lab each week. Part of the requirement for completion of the course is an individual project written up as if for submission to a journal. The results have been very gratifying and often lead to thesis projects or substantial parts of them.
I would be remiss if I failed to thank Randy Thomas who suffered through my initial few successes and many failures while doing his doctoral thesis with me. He was gracious enough to forgive me for the many times I had initially rejected what turned out to be some of the most crucial ideas now used in the simulations. Among many others, I wish to thank Mark Fidelman, Roy Caplan, Dieter Walz, David Scriven, Elisabeth Mintz, John Wyatt, Michel Thellier, Barry Bunow, John DeSimone, Fritz Sauer, Kamlesh Thakker, Court White, Dave Goldman, Ernst Huff, Jim May, Don Oken, Joe Feher, Hans Westerhoff, Daniella Pietrobon, Matthew Witten, Michael Kohn, James Kay and Sheella Mierson for significant contributions. I also wish to remember a dear friend and colleague, the late Claude Gary-Bobo, for having given so much to these developments. A special role was played by Stanislaw Przstalski, who, over many years, including some difficult times, organized the School on Biophysics of Membrane Transport in various places in Poland. These schools were among the most productive sites of international collaboration I have ever experienced. In the same spirit thanks to many already mentioned for the workshops on biothermokinetics which were equally fruitful.
Particular gratitude is due to the people who have made the computer work possible. The persons in the Health Science Computer Center at the Medical College of Virginia Commonwealth University have always been a great help. The willingness of the University to provide these services to so many of us has been responsible for these results as much as any other factor.
My thanks to the editorial staff of New York University Press for their patience with me. I kept them waiting much longer than I care to mention, partially because of some the part of university life we all wish we could find a way to do away with and partially because I am always very unrealistic about the magnitude of the tasks to which I commit myself.
I also wish to thank and formally acknowledge the following publishers for permission to use their material in this book: Marcell Dekker, Inc. for portions of chapter 1 of Jacob Marinsky's book Ion Exchange, 1966; J. C. Baltzer, AG, for portions of my paper co- authored by F. Sauer in J. Math. Chem. 2, 1988; Garland Publishing, Inc., for figure 2-35 of The Molecular Biology of the Cell, by Alberts, et al.
This list is incomplete and I apologize to anyone I omitted. One omission can not be permitted, however. I owe a special note of thanks to so many colleagues who, for various reasons, were (and may still be) skeptical of the approach. Without that skepticism and close scrutiny, there would be far more weaknesses and errors in this and related works. Those who know me know that I love a good argument, often to the point of becoming very excited. I hope that trait is never construed as a lack of appreciation for opposition to one of my pet ideas. For that reason, this acknowledgement to those who were willing to try to get me to see... is especially heart felt. We are a very special community in that without the dialectic, we would be so much less that we are. I hope we never lose that quality. In the same spirit, I hope this book provokes some strong reactions, positive and negative!
Donald C. Mikulecky
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