Robert Irwin Macey

Bob Macey, an expert in generating and applying mathematical methods for studying biological membranes and for teaching physiological and pharmacological principles, died at his home in Berkeley on June 2, 2020 from complications associated with Parkinson's Disease and high blood pressure. Bob's research career was characterized by his innovative experimental methods and insightful conclusions about the permeation of biological molecules including water, urea, and ions across cell membranes, and the application of these findings for the clarification of important physiological phenomena. Bob's teaching career was characterized by his novel approaches to teaching physiology, especially his unique abilities to apply quantitative mathematical analysis to understanding complicated physiological interactions. Bob was also a mentor who provided unique and valuable advice and insights to his students, family, and friends.

Bob was born on September 22, 1926, and grew up in Minneapolis, MN. His mother, Ella Silverman, and father, Joseph Macey, were both from Minnesota (she from Minneapolis, and he from St. Paul). Bob's father died in a car accident when Bob was still in college, and Ella moved to Washington, DC following his death. Bob completed all of his early schooling in Minneapolis and received a B.A. degree in biochemistry from the University of Minnesota in 1947. By the time he had graduated, Bob had developed a strong interest and ability in mathematics, and, following a year's hiatus when he immersed himself in the art and music scenes in New York City, he entered graduate school in the new field of mathematical biology at the University of Chicago in 1949. Bob's Ph.D. adviser there was Nicolas Rashevsky, often referred to as the "father of mathematical biophysics and theoretical biology."

While still in graduate school and before he had completed his Ph.D. thesis, Bob served as an instructor in chemistry and physiology at George Williams College in Chicago, then as an instructor in mathematics at Illinois Institute of Technology. He performed postdoctoral research at the Aeromedical Lab at the University of Illinois from 1955 to 1957 and was then recruited to the physiology department at the University of Illinois Medical School, where he stayed from 1957 to 1960. He was recruited to the department of physiology (later physiology-anatomy) at UC Berkeley by Israel Chaikoff, chairman of the department at the time. Bob rose up the academic ladder from assistant to associate to full professor at Berkeley by 1969. He served as chairman of the physiology-anatomy department from 1984 to 1989 and finished his formal academic career in the newly established department of molecular and cell biology (MCB-biophysics and cell physiology division) in 1991. Bob served as a very engaged emeritus professor by teaching his modeling course in MCB from 1991 to 2012. He maintained long-term collaborations in research and teaching abroad, serving as an invited professor at the New University of Lisbon from 1979 to 2003.

Bob's research was focused on understanding how small, biologically important molecules permeate the membranes surrounding animal and plant cells and their organelles. Over the course of his career, he published over 80 papers detailing research on frog skin, crayfish giant axons, red blood cells, mitochondria and chloroplasts, and on membranes vesicles isolated from kidney and intestinal epithelia. Small molecules like water, urea, and ions permeate biological membranes very rapidly and can equilibrate inside and outside cells in seconds or even milliseconds, making it very difficult to measure their permeability properties. Bob and his students and collaborators applied novel methods (e.g., stop-flow assays, nuclear magnetic resonance, electron spin resonance) that could be used in combination with clever experimental procedures (e.g., rapid kinetics, high pressure, radiation inactivation) to accurately measure permeation of these polar, hydrophilic molecules across cell and organelle membranes and thereby obtain information about the permeation mechanisms involved. Did the molecules primarily diffuse across the hydrophobic lipids or were there specialized protein carriers or pores that facilitated their permeation? How large were the pathways responsible for the permeation of substances across the membranes? Bob's studies were performed at a time when the molecular structures of membrane transport proteins were unknown, so experiments had to be designed and performed carefully to understand and characterize these mechanisms. His studies showed unequivocally that water moved through a channel or pore that was highly selective for water (excluding all other molecules), while urea moved across red cell membranes associated with a carrier protein that excluded water. At the time this was a controversial conclusion, but it was shown to be correct.

Further studies on the water pores showed that they were blocked by PCMBS, a chemical that selectively bound to a sulfur-containing amino acid within each water pore. Bob and colleagues also showed that the water pores fluctuated between an open state (normal 0peration) or closed state (e.g., induced by PCMBS) and that 11 water molecules moved through each open pore, one molecule following the next in a single-file manner. These studies provided the unique conclusion that water channels and ion channels in cells were similar in that both were selective for the specific molecules that permeated and both exhibited open-closed configurations, but water channels excluded ions, while ion channels often allowed water molecules also to permeate.

These studies provided the experimental groundwork that was later built on by Peter Agre, who won a Nobel Prize in Physiology and Medicine for his identification of the specific red cell membrane protein that, as Bob's work predicted, served as the selective pathway for water movements across red cell membranes. The protein family was named aquaporins, and Bob's research was central to identification of these proteins that are ubiquitous in nature and present in nearly every cell in the human body and in most other organisms, from bacteria to yeast to humans. After the discovery that aquaporins were widely distributed in human tissues, Bob's work in membrane vesicles prepared from several types of epithelial cells unmasked the presence of a difference in hydrostatic pressure between the inside and outside of animal cells, a fact that was unknown at the time. The resulting membrane surface tension was found to act as a regulator of water channel activity. Bob's work describing urea and water permeation also clarified the importance of volume stability of red blood cells passing through the inner medulla of the kidney and of the volume control mechanisms that operate in the proximal tubule cells of the kidney.

At the start of the millennium, the first aquaporin crystallographic structures showed that the channel had a very narrow pore, and molecular dynamic simulation studies showed 11 water molecules in a single file inside the channel, just as Bob's work had predicted almost 20 years before. Bob and his colleagues also applied his novel approaches to study permeation of ions across biological membranes through the anion (Cl^- and HCO₃^-) exchanger, Na/K-ATPase (Na/K-ATPase/pump) and K⁺ ion channels, all of which serve important functions in nearly all animal cells. He also used electrophysiological and radioactive tracer methods in pioneering work that provided unique insights into ion movements across frog skin epithelium and crayfish nerve axons. Bob applied whatever method was appropriate to the question he was investigating. 

Bob was an inspiring teacher for students of physiology at all levels and in any format: large lectures for beginning and advanced undergraduate students, small seminars for graduate students, and individual discussions of research data and plans for the future. He had a unique ability to present complicated, quantitative aspects of physiology clearly and in ways that encouraged understanding of basic principles instead of memorization, so that students could apply their knowledge to new physiological situations. He wrote three textbooks for introductory students in physiology, including the Physiology Coloring Book (co-authored with Wayne Kapit and Essai Meissami), which used an innovative and engaging way to present basic concepts in physiology; concise summaries of physiological systems are presented in one or two pages, including terrific drawings by Kapit that students could then color themselves. Bob was convinced that physically interacting with the drawings ensured better understanding of the principles. Graduate students and researchers on biological transport still consult his chapter on "Basic Principles of Transport" (co-authored with Teresa Moura) in the Handbook of Physiology, Cell Physiology. As a colleague/collaborator in research, Bob was an inspiring partner, always vigorously and passionately discussing new ideas until common grounds were met, making research with him a very rewarding process. He was also very accommodating to his students and postdoctoral fellows in allowing them to investigate problems outside the major interest of his lab. Bob always placed the long-term goals of his students at the forefront of his considerations.

One of Bob's greatest passions and accomplishments was developing the mathematical modeling software Berkeley Madonna, which he co-created with his UC Berkeley colleague George Oster. In the mid 1990s, aided by both NSF and NIH grants, Bob and George developed software intended for users to easily construct complex mathematical models and solve them quickly on a personal computer. From the beginning, Bob and George used Berkeley Madonna to teach complex concepts in mathematical biology to undergraduates. Bob was committed to making Berkeley Madonna easy and intuitive to use so that students could focus on the biological concepts without getting bogged down in difficult mathematics. Once a model was made and solutions graphed, he then led students through potential changes to the model and had them replot graphs and critically interpret what they were seeing and how it related to the underlying biology. In addition to teaching the ins and outs of Berkeley Madonna at UC Berkeley, Bob also taught courses in using the software for all aspects of physiological modeling at the Gulbenkian Institute in Porto, Portugal.

Berkeley Madonna is not only a tool for education, but its speed and ease of use has attracted many scientific researchers throughout the world from academia, non-profit and government organizations, and industry. Each year there are about 150-180 publications and patents published that employ the software on such varied topics as conservation efforts for green sea turtles to battery development for the European Union's Mars Express spacecraft. Perhaps the largest user base is in the pharmaceutical industry, where extensive use is made of Berkeley Madonna in the construction of pharmacokinetic/pharmacodynamic models that track the time course of drugs throughout the body.

In the last years of his life, Bob continued to dedicate time to Berkeley Madonna, helping to obtain an NIH SBIR grant in 2019 to push the software in new directions, and working with his small team to implement tools that will help model individual differences important for personalized medicine. Just before his passing, a new version of the software (version 10) was released, moving it from 32-bit to 64-bit – a major accomplishment that was Bob's primary scientific goal for the last 10 years and essential for the future of Berkeley Madonna, as operating systems are phasing out 32-bit software.

In addition to his formal teaching and research accomplishments, Bob was a wise, kind, and trusted mentor to his many students and postdocs and even to faculty colleagues, who often asked for his advice about everything from negotiating the maze of academia leading towards tenure to family issues. Many of these advising sessions were memorable because of the breadth of topics and useful information imparted. Bob had a wonderfully positive, kind, and self-deprecating attitude that he used to great effect when advising and supporting colleagues and friends. It was not unusual for conversations to veer into a wide range of topics from national politics to university intrigues, personal relationships, expanding one's mind and consciousness, music (he loved jazz, especially Coleman Hawkins, whom he modeled when he learned how to play the saxophone), the theater, and art of all kinds. Bob also had an infectious sense of humor, not to tell jokes, but to offer wry comments about life that lightened everyone's mood. You could see his positive attitude in the twinkle in his eyes and the wry smile that creased his mouth. Everyone left interactions with Bob feeling uplifted and as though they had learned something good about both themselves and about life.

Bob met his wife Anne when he was a graduate student at the University of Chicago, and they married in 1956. Bob and Anne had two children, J. Robert, a geneticist at Merritt Junior College and the Museum of Vertebrate Zoology at UC Berkeley, and Laura, a graphic artist in Silicon Valley. Bob and Anne separated in 1971, but they never divorced. Anne died in 2012. Bob also remained close to his two sisters. Beverly (Elkan) was a dedicated psychologist and moved into one of the cottages that Bob owned on Spruce Street – she died in 2019. Gerry (Krieger), a skilled painter and sculptor, died in 2010.

Bob met and lived with Christa Zvengintzov in Berkeley from 1982 until she died in 2012. Bob and Christa both loved the outdoors, including hiking and skiing in the Sierra Nevada and just hanging out together in their idyllic cottage on Spruce Street, with a beautiful view of the San Francisco Bay and surrounded by the garden that Christa designed and maintained. Bob and Christa had a full life together, filled with wonderfully varied interactions, discussions, and laughter. They also enjoyed traveling, especially to isolated hideaways in Portugal, Hawaii, and Bali.

Bob is survived by his daughter Laura, son J. Robert, two stepsons (Nick and Mischa Zvengintzov), a granddaughter, and three step-grandchildren.

Terry Machen
Michael Grabe
Teresa Moura
Daniel Karan
Lenore Wadzinski
2020