"A common trigger precipitates biological events as diverse as the contraction of a muscle and the secretion of a hormone. The trigger is a minute flux of calcium ions . . . knowledge of these intricacies may lead to a greater clinical control over intracellular calcium, a possibility that has broad implications for the treatment of disease. "
hese words introduce an article by E. Carafoli and J. T. Penniston, published last month in Scientific American. The excellent essay that follows summarizes for the educated lay reader an exploding biomedical research area: the study of calcium ions as signals, of calcium-binding proteins, and of their respective roles in the response of living cells to external stimuli. Many MBL scientists, among their peers around the world, chase these intricacies today. Should the quoted statement about disease strike you as mere piety, please note that the current New England Journal of Medicine includes two articles on dietary calcium and human cancer of the colon.
In scores of scientific papers, in lectures, and in three editions of his great textbook, An Outline of General Physiology, first published forty-eight years ago, an MBL scientist argued repeatedly for just such a role of calcium. This is a sample from the third and last edition (1952) of the Outline: "The sensitivity of protoplasm and its response to stimulation are believed to be due to a sensitivity to free calcium ion and it is believed that the freeing of calcium and the reaction of this calcium with the protoplasm inside the cell is the most basic of all protoplasmic reactions."
The words " . . . are believed to" and " . . . is believed" are code - in part an editorial modesty and in part a disguise for small numbers. They really stand for "I, and some of my students, old colleagues, and followers believe that . . ."
The author was Lewis Victor Heilbrunn. For many years his was the most distinguished textbook of its field. He was a productive investigator, a notably successful teacher of young scientists, an MBL Trustee; certainly one of the influential American biologists of his generation. Yet not many of his peers paid attention to the arguments about calcium, not even at the MBL, which was the summerplace of his adulthood. Director Frank R. Lillie, in an indispensable history of the MBL published in 1944, devoted the long, central chapter to a review of outstanding research done at Woods Hole. At the time of writing Heilbrunn was already one of the Laboratory's leading figures, but his work is not mentioned. Such failures, and the continued growth of interest in calcium as a trigger of cellular activity, may justify these additional thoughts, even though Heilbrunn was the subject, just a year ago, of an MBL Newsletter article by James Shreeve.
HEILBRUNN'S IDEAS about calcium and its role as the ionic trigger of cellular activities, from muscle contraction to glandular secretion, were ignored, or judged to be of no great importance, for more than thirty years. Today's insights would surely have come years earlier had his ideas not been ignored. He did receive research grants, but they were grudging and parsimonious support. He was a full Professor, but without much honor in his university. He got no honorific recognition from the larger community of biologists. He died too soon, in an automobile crash, and despite his denials, he had been embittered by the lack of recognition. How are we to explain the contradiction? Heilbrunn was right about the importance of calcium, about its uniqueness as an intracellular signal. To have reached and supported that conclusion was a very important achievement. He and his students contributed the strongest body of experimental evidence for it, in biological systems as different as frog muscles and algae. He was an impeccable scholar. His documentation, his citation of the work of others, were thorough beyond the imagining of a contemporary journal editor. The Outline of General Physiology had thousands of references. In the last edition, the Author Index ran to twenty-three pages of miniature type, three columns wide. Still Heilbrunn's mature work was not given serious attention by a majority of his peers. Even now, with calcium at center stage, his contributions are hardly ever cited. Not a few of his contemporaries poked fun at the preoccupation with calcium.
Science is supposed to be an intellectual process, an impersonal one, by which strong generalizations that are likely to be true catalyze new research, while unsupported generalizations are ignored or soon forgotten. Reproducibility and weight of results, scholarly acknowledgement of precedents_ these are supposed to insure success, whereas one-time phenomena and the failure to give due credit deserve and receive obloquy. On this score justice, scientific if not personal, seems to have eluded Heilbrunn and calcium. Why?
LV. HEILBRUNN WAS A lonely man, a man of contrasts. He was intelligent, fastidious, painfully honest, energetic and impatient. He could be abusive - at meetings and seminars, for example - and his remarks were as cutting as they were clever. He was a splendid teacher and spontaneously generous, sometimes at great personal sacrifice, to his students and others. He was a remarkable scholar. Yet he paid only casual attention to research that was off the track of his original and immediate interest. In any other profession such a man would have been called a genius.
Heilbrunn was committed to an outmoded way of thinking about cell chemistry and structure. He was unimpressed by the progress of biochemistry in the 1940s, especially of macromolecules such as proteins and nucleic acids. For him, as for his illustrious teachers, it was sufficient to think of "protoplasm," the stuff of living cells, as in the colloidal state; a supposedly distinct state of matter (i.e., on a par with liquid, solid, gas) dominated by surface forces rather than by chemistry. He was concerned with the living substance as an entity: the biochemists were content, for many years, to think of it as a bag of enzymes. He measured fundamental processes as alterations of viscosity or changes from sol to gel; the biochemists, by proper chemical endpoints.
He thought of blood-clotting, a process that takes place in solution but which, like so many cellular processes, is triggered by calcium ions, as a model of protoplasmic sol-gel changes, and he clung to the model long after it ceased to be applicable. Thinking in terms of reversible sol-gel transformations, rather than of molecules and architecture, he gave scant attention to the advances in cytology that came with the electron microscope.
His rejection of technology and instrumentation, justified originally by a proper but austere view of what constitutes science, became an insistence upon simplicity for its own sake. His experiments were sharp and clear, often with important conclusions, but they were also unfashionably simple - easy, almost. Toward the end, with biophysics and biochemistry, electron microscopy and X-ray crystallography exploding all around him, Heilbrunn stuck to his creaking hand-centrifuge, his finger bowls, and his microscope. He was fond of saying " . . . when the equipment gets bigger than the span of my arm, I am an engineer, not a biologist. "
New clubs and fashions grew up, weeds encroaching on the rosebush. He joined none of them. Clubmembers concerned themselves with club rules, club activities, and the emergent identity. They had little attention to spare for the activities of a professional, lifelong non-member. That his activities were important and relevant, and his basic claim sound, didn't matter. What did matter was his irritating adherence to colloid
chemical language, and his frequent allusions to the clotting of blood. Interest in the actions of calcium in cells soon fell by the wayside, displaced by other issues, by physical biochemistry, intermediary metabolism, ultrastructure, biochemical genetics.
HEILBRUNN'S WORK and its profound implications might be characterized, now, as "rediscovered;" but in a fundamental sense they have been forgotten. The modern biology of calcium has grown up almost independently of the older literature. What he proposed broadly as the role of calcium in cellular irritability was true, but appreciation of that truth has come almost independently of the original advocate. He got none of the honor he deserved for his originality, and when honors for calcium became available, it was too late. Heilbrunn was dead. The same plot fits many other scientific stories, stories of even greater ultimate significance. I think of Fourier, and of Mendel.
I have no epigrammatic close to this one for young investigators or lay persons. Perhaps they will consider, however, these few generalizations, which I know are true: Being right isn't enough. What you say, however right, must be said in a currently acceptable language, must not violate too brutally current taste, and must somehow signal your membership in a respectable professional club. If you want to succeed you must play all of the game, not just the innings in laboratory or library.
Finally, however, there is nothing really unexpected in the above. It's the way things are in all other professions. There is nothing inherently just or objective about the profession of science, in the short term. But, to begin with, biology does more to improve the human condition than most other professions. And objectivity does win. Not everybody gets a fair deal, but the truth comes out, eventually. And once it does, our understanding of the world is forever changed.