Keith Roberts Porter (1912 - 1997) - a brief biography and tribute to his career

• 1934, B.S.	Acadia University, Wolfville, Nova Scotia, Canada
  1938, Ph.D.	Harvard University, Boston
  1938-1939	Princeton University
  1939-1961	Rockefeller Institute for Medical Research, New York
  1961-1970	Harvard University, Boston
  1968-1984	University of Colorado, Boulder
  1984-1987	University of Maryland, Baltimore County, Catonsville
  1987-1997	University of Pennsylvania, Philadelphia

Keith Roberts Porter (1912-1997) is considered by many as the "Father" of the field of cell biology. He was born in Yarmouth, Nova Scotia, and graduated from Acadia University in 1934. He received his Ph.D. from Harvard University in 1938, where he studied amphibian embryology.

The Biology Seminar at Harvard University, about 1936 (Keith Porter is second on the left)

After graduating from Harvard, Porter spent 1 year at Princeton University as a research fellow. In 1939, he moved to The Rockefeller Institute for Medical Research in New York City, joining the laboratory of James B. Murphy. Porter's initial goal at Rockefeller was to set up tissue cultures for use in Murphy's studies of cancer. Indirectly this work led to the first use of the electron microscope for the study of cell structure. A landmark first EM image of an intact cell was made by Porter, Claude, and Fullam in 1944 and published the following year (see image below; double click on this image to see a higher resolution view). This and similar images launched the field that came to be known as cell fine structure or ultrastructure and that revolutionized the study of cell structure. Over the following decade, Porter and his colleagues developed many of the critical techniques of specimen preparation that made electron microscopy of cells possible and that are still in use today. By 1953, the key procedures for EM study of cell fine structure had been worked out, and such studies had become routine at Rockefeller and and in several other laboratories around the world.

Porter founded the first major journal in cell biology, the Journal of Biophysical and Biochemical Cytology, which later changed its name to the Journal of Cell Biology. He also participated centrally in the founding of the American Society for Cell Biology and of the Electron Microscopy Society of America, now the Microscopy Society of America. After the Rockefeller years, Porter's career extended to Harvard University, to the University of Colorado, to the University of Maryland, and, finally, to the University of Pennsylvania. Dozens of students and post-doctoral investigators passed through his laboratories, benefiting from his wisdom, his examples of dedication to his work, and the high standards he set for microscopy. He leaves a heritage of immeasurable influence on biology, both in his own work and publications, and through the many students and colleagues who were fortunate enough to work with him. Keith Porter died on May 2, 1997 in Bryn Mawr, PA, and was buried in Pleasant Valley, Nova Scotia, near his childhood home of Yarmouth.

Keith Porter's achievements and contributions to modern cell biology are manifold. His early studies of cell structure using electon microscopy, in the 1940s, initiated decades of cell fine structure studies and contributed critically to an appreciation of the importance of understanding the relationships between cell structure and cell function. By 1943, Albert Claude and Ernest Fullam had already used electron microscopy to examine isolated cell fractions, in partucular the fraction Claude had named the "microsomes." But at the time it did not seem possible to look at intact cells because they were too thick to be penetrated by the beam of the electron microscopes of the time, which had an energy of only about 50 KeV. Porter, however, quickly realized that the cells he was growing in culture might be thin enough to be examined effectively in the electron microscope, since often the margins of these cells spread out in a thin layer over the substrate on which they were growing. Before this study could be done, however, Porter had to solve a number of problems in specimen preparation. The cells had to be mounted over the holes in metal specimen screens, and this he did using thin plastic films. The cells had to be fixed, and for this he chose a method involving osmium tetroxide. This had been shown earlier to produce minimal changes in light scattering as seen in dark-field light microscopy, suggesting that there was little alteration of very small cellular structures. These cells were dried, in these very early studies, by the simple expedient of leaving them exposed to room air once they had been plated onto the specimen screens and fixed.

This combination of choosing the right kind of cells, and applying suitable preparation methods to the cells led to the first useful images of the internal structure of cells at resolutions exceeding by a hundred fold or more what had been attainable in the light microscope (see image at the left). This also led to the immediate description of an important cytoplasmic organelle, later was named the endoplasmic reticulum (ER) by Keith Porter and George Palade, and to their realization that this organelle was the intact cell's equivalent of Claude's isolated microsomes. These early results were first reported in 1945 in the Journal of Experimental Medicine, where the landmark image at the left first was published.

Porter used these methods to look at a variety of types of intact cells, including tumor cells and virus-transformed cells. An important result during this period was the observation that the Bittner milk agent, which would transfer mammary tumors in mice, was very likely associated with a defined particle of uniform size that could be seen in electron micrographs of infected cell cultures.

In 1950, Porter began a series of studies on muscle, a tissue that was to reappear again in his later work. A study of the contraction of isolated myofibrils, where the quality of the images suffered badly from excessive thickness, stimulated his interest in exploring thin sectioning methods that could be applied to embedded tissues, modifying procedures used for preparing thicker sections of tissues for light microscopy. Porter spent a summer in the laboratory of H. S. Bennett in Seattle trying to cut thin sections on an ordinary microtome using a steel knife, and using thermal advance instead of the usual mechanical system to provide the fine advance needed. The rather unsatisfactory results he got seemed to convince him of the need for better instrumentation for thin sectioning, and he devoted considerable effort in the early 1950s toward that goal. These efforts culminated in the introduction of the Porter-Blum microtome in 1953, an instrument that, while not the first, remained a standard for several decades and provided the basis for models still in production today.

At this point, Porter and the group of biological electron microscopists that had grown up in the decade following 1945 left the study of whole cells grown in culture and focused their attention on the potentially more fruitful study of thin sections of fixed and embedded cells and tissues. One of Porter's early and important papers in this era reported the fine structure of ciliated epithelia, including the regularly-arranged array of microtubules that extend along the length of each cilium. This paper clearly demonstrated the tremendous potential that the electron microscope could offer in revealing details within structures, such as cilia, that were so small that even the whole cilium could barely be detected by classical light microscopic methods. Much smaller substructures contained with the cilia could be seen clearly, and with time the details of the arrangement of these internal microtubules were worked out. In fact, it was Keith Porter who first showed that there are 13 subunits in each of these microtubules, of which there are eleven within a single cilium, though it was several more years before structures at that level of fineness could clearly be resolved.

Once the thin section approach to electron microscopy of biological material had become well-established, Porter's interest concentrated on a few cell organelles. The ER was one of these. Porter, and George Palade, elucidated the structure of this intracellular membrane system in a variety of specialized cell types. A notable case is in the striated muscle cell, where he and Palade named the equivalent organelle the sarcoplasmic reticulum or SR for short. In muscle cells, the SR is now known to accumulate calcium in the cell at rest, and to release some of this calcium as a key step in bringing the cell from rest into a state of active contraction. In many other types of cells the endoplasmic reticulum plays a central role in protein systhesis and secretion of proteins, and Porter's initial observations formed the basis for studies of this important cell process. Another specialized function of the endoplasmic reticulum in some cells, as for example the cells of the liver, is the detoxification of drugs and other toxic compounds, and this was first recognized by Porter in 1959.

Several of Porter's studies were concerned with the cell surface and its associated structures. In animal cells, he studied connective tissue and its extracellular collagen fibrils, and in plant cells, it was cellulose. He provided important insight into how complex tissue architecture can be influenced, and prehaps determined, by process whereby these compounds are synthesized within cells and secreted through their surfaces in an organized way. Two new organelles whose discovery can be attributed to Porter and his collaborators are the autolysosomes and coated vesicles. The former were found in cells of the liver, and it was recognized that they are important in the degredation of cell structures, fragments of which could be found inside them. Coated pits and vesicles were first found by Porter in oocytes, and subsequently have many times been inplicated in the selective uptake of proteins into cells, and idea first put forth by Porter.

Porter's work on microtubules and their role in the determination of cell form began with studies in plant cells. Soon after, they were recognized in almost all cell types in studies in many laboratories. It was Keith Porter who first pointed out that microtubules appear to be centrally involved in the determination of many kinds of cell shape and in aiding or causing alterations of cell shape. This idea has been carried on by an enthusiastic group of workers, and their students in turn, many of them inspired by collaboration with Porter when he was at Harvard University.

Porter's interest in muscle cells, and in the cell surface, reappeared in his collaborative studies of the special differentiations of the muscle cell surface. The discovery of the nature of the inward extensions of the muscle cell surface, known as the transverse tubules, opened up an important area of muscle cell structural and functional studies concerned with the inward spread of contraction activation into striated muscle cells. Again, much of this work was carrien on in the careers of younger people who acquired the Porter enthusiasm for research in his laboratory.

This period in Porter's career, extending from the early 1950s to the late 1960s, produced more than 100 publications in his name and countless others by students, collaborators, and others who followed his pattern and applied it to subjects of their own interest.

In the early 1970s, Porter began producing remarkable pictures of cells with a new kind of electron microscope, the scanning electron microscope. In retrospect, this is even more remarkable than it seemed at the time, for these instruments had been available, expecially in England, for more than a decade, but they had been used by very few biologists except for some obvious specimens such as insect eyes and specialized skin surfaces of amphibians and reptiles, where it was the already exposed surface of the object that was of interest. It appears, once again, to have taken the Porter combination of wisdon and insight to realize that most tissues would need special preparation methods to bring them under study by this surface-imaging instrument. First he resurrected the critical point drying method, discovered by Tom Anderson in the 1950s, which has the capability of drying delicate tissues without the crushing effects of surface tension. Then he applied this method to both tissue culture cells and to cells freed from organs and tissues by chemical and enzymatic treatment. Once again, the scientific world was treated to new views of cell surfaces never seen before. And, once again, the Porter lead was picked up by many others, and this method quickly took its place in the armementarium used (and now taken for granted) by cell biologists everywhere, just as the thin sectioning method had done two decades earlier.

A third, parallel story can be told with respect to high voltage electron microscopy. Once again, these instruments had been available, in a limited way to be sure, for several years, but had not been applied very successfully or regularly to biological specimens. Keith Porter stepped in and was instumental in convincing the biological community and funding agencies that high voltage electron microscopes should be explored more seriously in biology. The result was, first, a program that allowed a few interested scientists access to the 1 million volt instrument at the U.S. Steel laboratories in Monroeville, where it was used to study metallic specimens under the direction of Robert Fisher. This led directly to a program, sponsored by the Division of Research Resources of N.I.H., that provided three 1 million volt microscopes for biological research, one at the University of Colorado, under Porter's direction, one at the University of Wisconsin under Hans Ris, and a third at the N. Y. State Dept. of Health under Don Parsons. These three nationally-available facilities within a few years clearly demonstrated the ability of the higher accelerating voltages to provide clear images of whole cells and of sections up to several micrometers in thickness, resulting in greatly improved understanding of the three-dimensional nature of cellular structures.

A sort of final chapter in the career of Keith Porter unfolded in the last couple of decades of his life. His success with the high voltage electron microscope led him to return to an old love of his, the nature of the ground cytoplasm. Following the introduction of thin sectioning methods in the 1950s, attention had become focused on the formed organelles in the cytoplasm, especially those consisting of membranes. What lies between these formed organelles has veen referred to variously as the cytoplasmic ground substance or the cytoplasmic matrix. For many years it was thought to have little structure and to be of little interest. Once Porter started to use the HVEM to look at whole cells, with which he had started his career in electron microscopy many years earlier, he again took notice of this forgotten component of cells, and found it to be rich in structure. The exact nature of this structure was difficult to describe, and this led to considerable controversy over what it was, or even if it was real. Porter like to refer to it as "microtrabecular" in structure, and he made the important observation that most, but not all, of the formed organelles in the cell were closely associated with this structure, and he speculated on how this interaction might contribute to cell form and to the control and distribution of materials in different regions of the cell. Most notable for their failure to participate, structurally at least, in this association, were the mitochondria, and it was tempting to think that this might somehow be related to the presumed extracellular and possibly symbiotic origin of these elements. From our present point of view, while we still cannot "describe" the structure of Porter's microtrabeculae with the same simplicity as we can describe the ER, or mitochondria, the finding of so many new cytoplasmic proteins over the last decade or so, and discovering how these proteins form complex and specific associations with each other and with the organelles, certainly suggests that there is a structure at this level in the cell, as Porter was convinced there was.

Keith Porter's direct contributions to cell science through his own publications, both on methods of study and on the results of his studies, have been unusually extensive, diverse, and important. He has made another, and perhaps even more lasting, contribution indirectly through the many people he trained and with whom he shared his vast knowledge and wisdom. His former fellows and students are found in important positions at many outstanding universities throughout the world. At least 30 post-doctoral associates, and almost as many graduate students, have received direct training with Porter, and this has imprinted his style, drive, and curiosity on their careers. Through his example and publications, he has set patterns and high technical standards that uncountable other workers, many of whom may never have met the man, have followed. By the end of his more than 60 years as a scientist, his scientific children have had their own children, his grandchildren, and further generations are on the way.

Beyond Porter's science and his direct education of students and fellows, he also contributed greatly to the superstructure of cell biology. He was the driving force behind the founding of the Tissue Culture Society, the American Society for Cell Biology, the Journal of Cell Biology, and the International Federation for Cell Biology, whose first meeting he chaired in Boston in September, 1976, appearing at one of the functions dressed as Benjamin Franklin (he had the right build, but was in the wrong city).

One could perhaps characterize Keith Porter as a scientist who had a habit of being in the right place at the right time. The implication of an element of luck, however, is not consistent with the large number and great diversity of contributions he made. He may have been at the right places at the right times, but he seemed to have known where to go, and he knew what to do when he got there. One might also be tempted to characterize his career as one of moving into an area, staying for a time, and moving on. This is a valid characterization, but if it carries an implication of superficiality, it is an incorrect characterization, even if his career has had an unusual amount of variety. Perhaps the best characterization would be to say that Keith Porter showed an unusual ability to recognize opportunities for advancement in knowledge, to explore those opportunities, and in doing so, to open further opportunities that others could follow. He would then find himself drawn away to a new challenge, probably one that had already been incubating for some time in his fertile mind. Therefore, it is more accurate to state that Porter's aggregate contribution to cell biology is one of tremendous breadth and variety, than it is to single out any one contribution as unusually important or significantly comprehensive to illustrate his entire distinguished career. This was part of the style of the man. Without this characteristic of doing several things at once and changing horses often, Keith Porter probably would not have become the father of quite such a large and successful field in modern biology as cell biology. But without a doubt, he is that parent!

In a more personal vein, Keith Porter never took flattery seriously, and rarely flattered others. He had a sharp sense of humor. Those who knew him well also knew that when he honored you with his barbs, it meant he thought you worth while; others feared his sharpness and even avoided it. He set high standards for himself and for his friends and colleagues. At the same time, he could be a kind and fair friend, and a wise advisor. His criticism could be direct and to the point, but it always was delivered with a laugh attached, perhaps because he felt uncomfortable criticizing others.

[This piece includes a considerable amount of material from an essay written by Lee Peachey for the nomination of Keith Porter for the Presidential Medal of Science. The complete medal nomination was prepared for the Microscopy Society of America by Ettienne deHarven. Porter received the Presidential Medal in 1977 from President Jimmy Carter.]

Keith Porter at the RCA electron microscope, about 1953