Chapter 2

Sweden & Wenner-Gren, Naples & Stazione Zoologica, Rockefeller & Paul Weiss, UCLA (1952-1957)

Overview
On arrival in Stockholm in Dec., 1952, I found living quarters very scare, but was fortunate to rent a room in an apartment from three elderly sisters, my domicile for my entire Stockholm sojourn. Although informed by Prof. Runnström, Director of the Wenner-Gren's Institute, that Tryggve Gustafson would be my mentor, in actuality I was entirely on my own. To obtain sea urchins I almost immediately visited the Stazione Zoologica in Naples.

There I obtained a room and board at the Albergo (Hotel) Virgilio, owned and hosted by a family of German extraction with the unflattering cognomen of Schmutz. They were very friendly and sociable, and I learned most of my limited Italian at meals and often by playing card games with them. Another sociable activity for me in Italy, and even more so in Sweden, was playing and being a spectator at contract bridge clubs.

At the Stazione I continued my sea urchin studies, collecting frozen extracts in vials and shipping them back to Stockholm, where I developed my chamber type laboratory freeze-dryer. This was used to reduce my extracts to a powder. That freeze-dryer became the prototype for the VirTis line, the successors of which are now in worldwide use. In Stockholm, I began correspondence about marketing such an instrument. The further course of related matters partly occupied my attention for the next 17 years, but more of that in Chap. 3.

I had become acquainted with the Swedish researcher, Dr. Jerker Porath, at Berkeley, and our paths crossed again on the vessel Stockholm. He invited me to visit and work in his lab at the U. of Uppsala at Tiselius' Biochemical Institute. His biochemical procedures subsequently were adopted worldwide. Eventually he succeeded Tiselius as the head of the Institute.

One day at the Wenner-Gren Institute in Sweden I met the visiting eminent American embryologist, Paul Weiss, one of the most powerful forces in American biological sciences. He invited me to work on projects of his choosing in his new Rockefeller Institute lab. In the end we compromised. I could work on my own projects on weekends and evenings. I little anticipated that his main project would be by far the most productive, while I eventually discontinued my project. My side projects, however, figured greatly in my subsequent studies.

On one occasion at dinner with the Runnströms, I met Runnström's daughter, Vera. She proved to be a good friend over the next 50 years. She was Technical Editor at Almquist & Wicksell, publishers of the journal, Experimental Cell Research (ECR). Five of my papers (some co-authored) on the results of my research in Sweden appeared in that journal over the years 1954-1956, as did my 1962 paper on the genesis of cytoplasmic streaming.

During a vacation from Stockholm in 1954, I met the American, Martin Dangott, in London. He was one of the world's premier professional bridge players, much addicted to high stakes rubber bridge. One evening during dinner together we met the famous violinist, Ivry Gitlis, just embarking on his career. As Martin also was a gifted violinist, we went to Ivry's hotel room where both took turns with short pieces on Ivry's violin.

In early 1955, in New York, I began studies at Rockefeller. Weiss asked me to formulate a mathematical model of his theory on growth and growth control. Success finally was achieved after many months and false starts. Even so, it remained to verify the manual integration. Here we were fortunate. The electronics group at Rockefeller had just pioneered an ideally adapted analog computer, which quickly confirmed the integration.

The criterion of success, however, lay in the degree to which the equations reproduced experimental figures for compensatory organ growth. There, the model also proved to be highly successful. The project culminated with my giving a seminar at the Institute (by then a University). Further recognition came in 1965 when I presented a paper on the studies at the Third Annual Symposium on Biomathematics and Computer Science in the Life Sciences at the U. of Texas at Houston.

The highlight of the Symposium for me was visiting with Stanislaw M. Ulam, a key member of the now legendary Polish School of Mathematics. Together with John von Neumann, Ulam named and first used the famous 'Monte Carlo' method. In an informal discussion with Ulam I learned that we shared identical views on some mathematical or related issue, the precise nature of which I cannot recall.

Another avenue with great future implications for me opened at Rockefeller, eventually resulting in three books in a new field, analytical symmetry. I had met a highly talented Swedish machinist and engineer, Nils Jernberg, head of the Rockefeller Instrumentation Facility. We subsequently collaborated on several private projects. When Dr. Aron Moscona, another researcher, learned that Jernberg and I were collaborating, he asked if we could design and build a laboratory shaker for him without the existing limitations of harmonic motion.

I soon converted a standard harmonic motion generator into an anharmonic one. But neither Nils nor I was sure it would work before we actually built and tested it. The patent examiner, himself, could not fathom how it worked. A patent was issued in 1961, but only after I demonstrated a working model, receiving a congratulatory handshake afterward from the examiner.

The shaker driving mechanism was also sufficiently novel to receive a patent. It also could have been employed as a toy for drawing fascinating curves. To my surprise, when we tested the shaker, the curves followed by its platform were completely new to geometry, as also was the transformation that produced them. Who could have guessed that unknown curves would be obtained using simple transformations of conic sections?

On one occasion while at UCLA in 1965, I visited a commercial exhibit featuring shakers by the New Brunswick Scientific Co, Inc. To make a long story short, Nils and I eventually assigned production of our shaker to Mr. David Freedman, their president. Without implying premeditation, after stalling us for the next 6 years and incorporating some of the features of our shaker into his product line, without remuneration to us, he never did produce our shaker.

Unfortunately, I was unable to pursue the matter to a satisfactory conclusion, because I had many other irons in the fire. In addition to a full load of research and teaching at UCLA, I wrote three books on biological membranes and the physical chemistry of water, was engaged with Nils in manufacturing and marketing fluid dispensers, and was pursuing a legal action against the VirTis Company, in the matter of royalties on my chamber-type freeze-dryer.

After arriving at Rockefeller in 1955, I began to make plans to resume my research with sea urchins. My previous studies along these lines had led to publication of two book chapters: To resume these studies, I constructed another freeze-dryer unit, whereupon I contacted Mr. Wechsler at Palo to commercialize it. Not having the facilities to do so, he put me in contact with the VirTis Company, leading to the 17-year episode that I refer to in chap. 3 as "The VirTis Affair."

For the years 1957-1958 I was invited by Henry Allen Moe, secretary of the Foundation, to apply for a Guggenheim Fellowship, but declined the invitation, as I was anxious to return to Los Angeles. At that time, I wrote to UCLA inquiring about a position in the Zoology Dept. The Dept. Chair, Prof. Ted Jahn, invited me to give a Departmental seminar on my studies of growth and growth control with Weiss. An offer of an Assistant Professorship followed in July, 1957, which I accepted.

My initial teaching assignment was to take over Jahn's course in Cellular Physiology, while he was on sabbatical, as well as to give a course in Invertebrate Embryology. My plan was to continue sea urchin studies with material collected at Woods Hole while at Rockefeller, for which I had obtained a grant from the National Science Foundation. But first, I completed the growth studies, which eventuated in two further papers. The 3rd and last paper in the series, investigating the complete range of conditions to which the model applies, appeared as a book chapter in 1964.

In early 1961, Ken Norris, UCLA's herpetologist and marine mammalogist, and I combined forces to monitor small desert reptiles that burrow in sand. By means of capacitance changes that detune radio-frequency oscillator grids, with which submerged reptiles animals came into contact while burrowing, we were able to record their movements, opening a new dimension of reptilian activity studies. We put these techniques to use again in 1966, studying western shovel-nosed snakes.

Around 1961, I became interested in the matter of how much sleep was needed to stay healthy and function normally. I decided to investigate this matter with my pet deer mice. These studies revealed that the mice are highly adaptable. With numerous examples of their resourcefulness before me, I carried out some further experiments to probe the depths of their capabilities.

I instituted a program in which a light was turned on, say, every 10 min., but could be turned off by pressing a lever. As soon as a mouse learned how to turn the light off, it did so at every opportunity, within seconds of its coming on. The same result was obtained with sound. If the experiment is reversed and light or sound is turned off every 10 minutes, the mice turn them back on. Thus, the animals find it rewarding to control aspects of their environment, regardless of whether the aspects, themselves, are rewarding or mildly aversive.

These observations were of such great interest that I transferred my studies from sea urchins to small mammals. I published much more extensive studies of small mammals in 1962 in the journal Ecology. However, my studies in animal behavior were not welcomed, at first, with open arms. Although the utility of the new techniques was extolled, and I received letters of high praise, otherwise, as a newcomer to the study of small mammals, I had to revise and resubmit my early papers more than once, presaging later experiences as I ventured into other new fields.
End Overview

Arrival in Sweden
On arrival in Göteborg, Sweden in Dec. 1952, I caught the train to Stockholm. It was the Christmas season, then, and I found rooms to be unobtainable. A travel agent took pity on me and offered to loan me her daughter's bedroom for a few nights. In case the reader is unaware, apartments in Stockholm (as in many European cities) are as scarce as hen's teeth and are handed down to relatives when death intervenes. I was fortunate in the next few days to obtain a room in an apartment on Gästrikegatan with three elderly sisters (Hulda, Helga, and Hedwig), two of them spinsters and the third a widow. That was my domicile for my entire Stockholm sojourn.

On visiting Prof. John Runnström, Director of the Wenner-Gren's Institute, he informed me that Tryggve Gustafson would be my mentor. Tryggve also worked on sea urchin embryos but was branching out into frogs (the African clawed frog, Xenopus laevis) at that time. In actuality, I was essentially entirely on my own. I had a small but adequate facility next to Tryggve's. My research could not begin until sea urchins were collected, so I journeyed in the Winter of 1953-54 to the Stazione Zoologica in Naples, one of Wenner-Gren's usual winter collecting sites.

For the first part of the trip, I obtained an auto ride with an organic chemist, Dr. Olaf Klamerth, from the U. of Heidelberg, to which he was returning. I had met him in Stockholm, researching at the Univ. of Stockholm on something to do with butter yellow. His wife, coincidentally, knew of me from Caltech, where she worked during the war years in the same Kellogg Radiation Laboratory where I was quartered initially. I lost track of Olaf subsequently, but his name lives on in his correspondence with Linus Pauling (Special Collections), as he had sought unsuccessfully to obtain a position at Caltech in 1952. On the way south, I managed to visit Denmark, Germany, Austria, and Switzerland, usually staying at small hotels, then and later, but sometimes in private homes.

For room and board in Naples, I obtained a room at the Albergo (Hotel) Virgilio at Corso Vittorio Emanuele 659, owned and run by a family with the unflattering cognomen of Schmutz. They were of German extraction, where their name means "dirt" but were largely of Italian birth. There was Mama, Yanna, Emma, Rita, and Bruno. They were very friendly and sociable, and I learned most of my limited Italian at meals and often playing card games with them after dinners.

Another sociable activity for me in Italy, and even more so in Sweden, was playing and being a spectator at contract bridge clubs. In Berkeley, I had the good fortune to know two fellow students, Fred Turner and Joseph Bechley, who were both expert contract bridge players and Life Masters. I partnered with both of them from time to time but was not in their class. Quick thinking is not, and never has been, my forte. Last I heard, Fred was in an Institution (demented) and I've lost track of Joe, despite searching for him through the American Contract Bridge League.. In Naples, I met several bridge players from Italy's International Competition Teams and was invited to play a few hands with them. I remember only the names Forquet and Chiaradia. In subsequent years there were scandals over cheating by some of the National teams. I don't remember Italy's team to have been an exception.

At the Stazione in Naples, I worked on free amino acid metabolism during early development of a different species of sea urchin (Paracentrotus lividus) than the one studied in Berkeley (Strongylocentrotus purpuratus), but using improved extraction techniques. The Stazione's collectors harvested urchins in the Gulf of Naples, on order. I met many other researchers at the Stazione, where we all lunched at a dining room table that ran the length of a long room. The Europeans at the table were highly adept at switching between their native tongues and English, French, German, Italian, or Spanish, as need be. Results of those studies were published in Experimental Cell Research (1954;7:530-557). [Years later, 2/24/70, I was asked to provide information, suggestions, and comments concerning the Stazione for "a conference of European Science Ministers called for by UNESCO in early 1970 where, among other things, they would examine essentials contributing to a successful International Zoological Station at Naples," by Dr. O. Skalová, Consultant to UNESCO.]

Though I worked alone on most of my studies, I always had the company of others from the Institute. Upon completion of my collecting, my frozen specimens were shipped back to the lab in Sweden. It was during the freeze-drying of extracts of these specimens there, in vials, that I developed my chamber type laboratory freeze-dryer. It became the prototype for the VirTis chamber-type freeze-dryer line, the successors of which are now in wide use in research and production facilities for biologicals and medicinals throughout the world. The first liquid air traps, reminiscent of my Sparks-Worthington glass mercury vapor vacuum pumps, were made for me by Swedish glassblowers whose shop was just across the street from my room in Stockholm on Gästrikegatan.

The story of the development of the chamber-type freeze-dryer was the old one of "necessity being the mother of invention." To obtain maximum accuracy I desired to work with equal numbers of embryos at each developmental stage. Accordingly, after fertilizing the eggs in a large volume of gently agitated sea water, to distribute the embryos uniformly, equal aliquots were transferred to vials, allowed to develop at constant temperature, and preserved at various stages. All further treatments before final assays occurred in these original vials, including freeze-drying. Conventionally, other workers made final comparisons on the basis of total nitrogen content of samples or equal weights of dried embryos, whereas mine were based on equal numbers of embryos in all my samples. Conventionally, small samples of substances were obtained by first bulk drying in trays or flasks, and weighing out the dried powders. I worked with the totality of dried embryos from each stage, with no need for transfers between containers for different treatments. I also introduced the technique of irradiating the frozen extracts with infrared (see Fig. 3-1) to increase the rate of water sublimation.

At that time I began a correspondence about marketing a laboratory freeze-dryer of the chamber type I had developed. On April 8, 1954, I wrote a letter to E. Machlett and Son, who were advertising manifold type freeze-dryers in Science. In this type of apparatus an evacuated condenser cooled with liquid air has side ports with ground-glass nipples to which flasks containing frozen material to be dried could be attached (see Figs. 3-2, & 3-4). Water sublimates from material in the flasks and collects on the condenser walls as ice. A disadvantage is that ambient water vapor freezes on the exterior of the flasks, slowing sublimation of the materials inside.

Machlett forwarded my letter to Mr. Hyman Wechsler at Palo Laboratory Supplies in New York City. On August 25, 1954. He wrote:

I shall be very glad to negotiate with your attorney, or through any means suggested by you, for the promotion and sale of your new freeze unit, on the basis of which royalties would be paid to you.

I sent him drawings and instructions on Sept. 21, and he informed me a week later that they were proceeding with the matter and had assigned the task of building a working model to one of his assistants. There the matter rested for some months until, by coincidence, New York and the Rockefeller Institute became my home fur two years. The further course of matters concerning my freeze-dryer and its marketing occupied part of my attention during the next 17 years, but more about that in Chap. 3.

I had become acquainted with a researcher from Sweden, Jerker Porath, at Berkeley and our paths crossed again on the vessel Stockholm en route to Sweden. I visited him in Uppsala at Tiselius' Biochemical Institute on several occasions. He was carrying out experiments on component separation using various adsorption techniques, some quite successfully. They subsequently were adopted in research labs throughout the world. I did not realize, at first, that he was working for his Swedish doctorate, which I though he already had. However, in Sweden, as in several European countries, requirements for the doctorate are more demanding than in the U.S. Eventually he actually succeeded Tiselius as the head of the Institute. Jerker invited me to carry out several experiments in his lab.

As a result of all my activities in Sweden I was able to pick up the language to the extent of its becoming my best foreign tongue. In part, this occurred at the Stockholm Bridge Club, where I spent a number of evenings and entered a few tournaments. There I met Jan Wohlin, Sweden's best player, and partnered with him several times. However, I 'let him down' in that partnership more often than I care to remember.

First contact with Paul Alfred Weiss
One day the Wenner-Gren's Institute was all abuzz with word that the eminent American embryologist, Paul A. Weiss, would be visiting. At that time, Weiss was one of the most powerful voices and forces in American biological sciences. Originally at the U. of Chicago, he then had established a large research facility at The Rockefeller Institute, founded a few months earlier in 1954. Of course, I was much interested to meet him and ask about the possibility of a postdoctoral appointment in his laboratory. We discussed that topic at some length. Although the subsequent talk around the Institute was that "Weiss was interested in Kavanau but Kavanau wasn't interested in Weiss," the fact of the matter was different.

I wanted to continue my sea urchin studies, but Weiss wanted me to work on projects of his choosing. In the end we compromised, Weiss offered me a position on the condition that I work on my own projects only on my own time, meaning mostly weekends and evenings. I little guessed that his proposed main project would turn out best for both of us. He had it in mind from the start to put me to work on formalizing his theory of growth and growth control, probably with knowledge of my successful Berkeley paper on enzyme kinetics. My sea urchin project, however, never came fully to fruition, eventually having to be set aside for work of higher priority in animal behavior. Side-interest projects at Rockefeller, however, figured greatly in the course of my future.

On one occasion, when I had dinner with the Runnström family at their apartment home in Stockholm, I met Runnström's daughter, Vera. She proved to be a good friend over the next 50 years. She was married to a chemist, Lembito Reio, who also became a good friend, and who eventually achieved a professorship at the Technical University in Uppsala. Vera was the Technical Editor at Almquist & Wicksell, publishers of the journal, Experimental Cell Research (ECR). Five of my papers (some co-authored) on the results of my research in Sweden appeared in that journal over the years 1954-1956.

Years later, my paper on the genesis of cytoplasmic streaming also appeared in ECR (1962;27:595-598). Of course, Vera provided great help with all of the manuscripts. Her path and mine crossed on several occasions over the following years, twice in America, as her duties at A&W, and other interests, kept her travelling. She was a linguist of sorts, being fluent in several languages. As a sideline she gave French night classes in Swedish at a local high school, several sessions of which I audited.

I provide here some excerpts from a letter from Vera regarding the above paper on ECR stationary, dated 4/30/62 to give an idea of the flavor of her life and times:

Indeed I owe you a letter, you kindly wrote me one year ago when I was in New York and now lately on April 2....It is wise of you to send your ms directly to Prof. Mazia. He is a most efficient editor and you will certainly get very competent review about your paper. I have not received it in the office yet, you will hear from us the routine way when this happens.

I am working rather much, although my activities have grown out now to embrace a very nice 2-room office in the Karolinka Institute where Prof. Caspersson has kindly given me working space. There are two full-time secretaries working for me, and it is good to see that my organization has materialized out from my little study at home when I did all my typing until late at night. ECR is still going strong, indeed the influence is growing. Mr. Jacoby of Academic Press had me over to London recently where we had some nice discussions and I have done quite a bit of travelling on behalf of my work, spent 8 days in London and all myself 4 days in Paris as a "dessert" middle March. Last fall I was in Switzerland for 10 days and saw a lot of chemistry people and also wrote a small article on the organization of Swiss chemical societies - rather dry for literature but quite appreciated by the members of the Swedish Chem. Soc.

Since July last year I am also with Ingeniörsvetenskapsacademien [Engineering Scientific Academy] and collaborating with the more or less non-existing editor of their journal. It is good and interesting, although not so dynamic as when I started working up ECR and Svensk Kemisk Tidskrift [ Journal of the Swedish Chemists' Association]. A lot of other odd jobs are filling my day, and the main line seems to have been publication - interesting and versatile.

Lembito is still in New Orleans, I think it would be a very good idea if he could be invited to give a talk in Los Angeles. He is due back to Sweden in Sept. but would - I assume - be delighted to make his way via California. Why don't you get in touch with him: Tulane Medical School, Dept. of Psychiatry and Neurology, New Orleans 12, LA. I know he has two publications in press from his work there and he is bound to have some interesting things to tell. So at least you would see him again in the US before we shall meet in Europe during your trip. I cannot go away again on such a long and expensive trip and there are various activities going on in the summer which I have to attend. [Lembito eventually did come to UCLA and spent 2 or 3 years at the Medical School. JLK]

Otherwise life is going on as usual. Tonight I am going to have some old friends from the [Wenner-Gren's] Institute over: Tore Hultin, Gunnar Lundblad and Elsa Wicklund. We shall "celebrate" the spring - today the weather is extremely nasty - 1° C and frost, northern wind, dripping cold of the nose. On top of that they found something wrong with the heating system of our house [apartment] so they have cut both the heating and the hot water!! No time for comedy. But it will pass and we shall look forward to the charming and infatuating Swedish spring which is bound to come some time at last. Otherwise, I have started playing the piano and am tormenting my neighbors with Bach's zweistimmige Inventiones and Czerny's Etudes. I am positive that my neighbors dislike me very much! My parents will be back from the U.S. middle May where they are touring, unfortunately not on the west coast. Best wishes, Sincerely,

I was able to take some vacation time from Stockholm in 1954, traveling in England and the Continent. In London, I happened to run into Martin Dangott, one the world's premier bridge players, much addicted to high stakes rubber bridge. I was able to watch him in a high-stakes game at the Cavendish Club on one afternoon. That evening we were having dinner at some small café, when we were approached by another American, the famous violinist, Ivry Gitlis, then just embarking on his career. As Martin also was a violinist, we went to Ivry's hotel room; both of them took turns with short pieces on Ivry's violin.

On that trip I visited friends at the Stazione in Naples, and my 'family' at Albergo Virgilio. Traveling in southern France I dropped in for a visit at the Laboratoire Arago of the University of Paris at Banyuls-Sur-Mer. In southern Spain, I spent some time at Majorca. My most interesting times, however, were in Sicily, where I walked the countryside far and wide, exchanging greetings with the friendly native passersby. On that trip, I only spent evenings in hotels as a last resort, sometimes being able to get a room with a private family, and visit with them in the evening. I was usually told that I presented a quite different picture than their prevailing impressions of American tourists.

At Rockefeller
In early 1955, I returned to America on the steamship Gripsholm. After a stop at Rockefeller and Palo in New York, I trained to Detroit to visit my many relatives there. On returning to Los Angeles, I spent some time with my family, then living in an apartment at the Park La Brea development. Back in New York, I found a small apartment on E. 79th Street on the East Side, and began my work at Rockefeller. I also had an opportunity then to renew my acquaintanceship with my former mentor at U. of Michigan, O. S. Duffendack, who, by coincidence, had become Director of Research at North American Philips (Norelco) at Briarcliff Manor, NY. [The next year, at Duffendack's instigation, the Guggenheim Foundation invited me to apply for a fellowship - two weeks past the deadline (Oct. 15) -- offering to allow me into Nov. to submit a late application. However, I had my sights set on a faculty position at UCLA.]

Laboratory facilities were generously provided by Weiss for my own studies, and he set me to work immediately to formulate a mathematical model of his theory on growth and growth control by negative feedback. Very briefly, his theory was that growth, both normal and compensatory, was regulated by negative feedback. This was brought about by inhibitory substances produced during the growth (Fig. 2-1, cartoon of Weiss' model drawn by Weiss, himself). These were thought to accumulate in increasing concentrations as growth proceeded, eventually reaching a level that halted growth by negative feedback.

Progress did not come easily. First, I had to set up the appropriate differential equations expressing my best assessment of the negative feedback circumstances, following the general proposal by Weiss. Then, using known measured weights for chicken growth as an approximation model for organ growth (with the liver in mind) I had to integrate the equations by hand with a desk calculator of the 10-decimal kind in existence in 1955-1956. Then, I reformulated the differential equations, guided by the nature of the early failures to fit the chicken growth curve.

By such trial and error, with more than a few false steps along the way, success finally was achieved. I eventually arrived at three simultaneous differential equations with realistic parameters (initial generative and differentiated masses, inhibitor decay rate, volume of body space occupied by inhibitors [blood volume], etc.). Even after this phase was completed, however, it remained to verify that the painstaking manual integration process was error free. Here we were fortunate that the electronics group at Rockefeller had just perfected an analog computer (essentially a resistor-capacitor device) that was ideally adapted to our needs. Test runs on it confirmed the validity of the manual integration.

The criterion of the operation's success, however, lay in the degree of the equations' accuracies in reproducing compensatory growth, for which many figures were available from experimental manipulations. Here it proved to be highly successful, bringing great satisfaction to Weiss, who had been backing his proposals with vigor, despite opposition skepticism, for some years. The project culminated with a seminar on its results that I gave to the faculty and students at the Institute (by then a University) and an article in the Journal of General Physiology (1957;41:1-47), titled, "A Theory of Growth and Growth Control in Mathematical Terms." I let Talbot Waterman's assessment, covered in the "Revolution for Biology" (American Scientist 1962;50:548-569), speak to its success, including results from two subsequent follow-up studies by me at UCLA employing an IBM digital computer.

Perhaps the most impressive applications of theoretical and mathematical techniques to living things have been cases where differential equations were set up to describe the various rate processes in the system, where these have been programmed into a computer which has carried out various experimental solutions of the simultaneous equations involved and where the predictions of such specific quantitative models were directly compared with the outcome of actual empirical tests....

One example comes from the area of developmental biology where Weiss and Kavanau have proposed a specific mathematical model for growth and differentiation, the predictions of which have undergone some empirical verifications. The model combines three differential equations representing processes which include a closed loop permitting negative feedback ultimately to regulate development in the adult steady state. These equations define the rates of change in generative mass, in differentiated mass and in an inhibitory component which is postulated to account for the ultimate slowing and stabilization of growth and differentiation. While equations for these processes are quite complicated in the general case (equations 1, 2, and 3), they can be considerably simplified if over-all growth is assumed to be essentially complete and only regenerative growth in the adult organism is considered.

Based on available data appropriate values have been assumed for the various coefficients of these equations and a digital computer program carried out to explore the implications of the mathematical model. When these are compared with empirical data of experiments on compensatory growth, the systems analysis predictions show a number of interesting correlations and suggest certain specific new experiments to provide a more rigorous test of the underlying hypothesis.

The growth control paper with Weiss proved to be the most cited paper of my career, with 285 citations in various books and journals in subsequent years. Was this merely because of the magic of the Weiss name? In this connection, only nine years earlier Weiss had published a sensational paper with Dr. H. B. Hisco, "Experiments on the Mechanism of Nerve Growth," that elicited an incredible 625 citations. This was the exciting paper that demonstrated neuroplasmic flow in nerve axons. Otherwise, Weiss' three most cited papers, all with two or more coauthors, garnered 92, 111, and 168 citations, still very far above average. My second-most cited paper was the 17-page review, "Behavior of Captive White-Footed Mice," in Science (1967;155:1623-1639), which received 143 citations (concerning which, more later).

Further recognition for the growth control studies materialized about ten years later when I was invited to attend the Third Annual Symposium on Biomathematics and Computer Science in the Life Sciences at the University of Texas at Houston, April 5-8, 1965, and to present a paper in the session on Mathematical Modeling; Biomedical Applications. The topic I chose was the Weiss-Kavanau model on growth and growth control. The highlight of the Symposium for me was having a chance to visit with Stanislaw M. Ulam (1909-1984), a key member of the now legendary Polish School of Mathematics who presented a paper on "Recursive Definitions of Static and Changing Patterns." Together with John von Neumann, Ulam named, and first used, the famous 'Monte Carlo' method.

Ulam is best known for his important work in the early history of nuclear weapons. It was his insight that revealed Edward Teller's early model of the H-bomb to be inadequate. Teller had invented a spherical hybrid design, the "Alarm clock," in which the fuel for a potential hydrogen bomb would instead boost the yield of a conventional atomic bomb, scheduled for testing in 1951. Ulam went on to devise a better method himself, making a complete redesign necessary.

He was the first to realize that you could place all the of H-bomb's components inside one casing, put a fission bomb at one end and thermonuclear material at the other, and use shock waves, to compress and detonate the core (the fusion fuel) of the bomb with far greater force than could be accomplished with the usual method.. Teller resisted this idea at first, then saw its merit, and suggested the use of radiation, an intense flood of x-rays from the fission bomb, rather than shock waves. In 1952 this breakthrough (the "Teller-Ulam principle") led to "Ivy Mike," a true fusion device that exploded with a yield nearly a thousand times that at Hiroshima. "Radiation implosion," as the method came to be called, has been the standard method of creating H-bombs ever since.

At any rate in a discussion with Ulam I was gratified to learn that we shared similar views on some contentious mathematical, or peripherally-related, issue, the precise nature of which I cannot now recall, despite many attempts.

Recent views on the mechanism of liver 'regeneration' (but not of its negative feedback control) depend on upregulating the production of growth factors, such as growth hormone, and the proliferation of hepatocytes. A news feature recently appeared in Science (2006, April 14, p. 178) titled, "Two Unexpected Players Add Twists to Liver's Comeback Story." We learn that:

....liver mass depends on one or more unidentified humoral signals that drive regeneration when liver functional capacity is diminished....the concentrations of bile acids in the liver help control both the start and end of liver regeneration.

A different research team published evidence that a different neurotransmitter, serotonin, also governs the liver's regrowth. Both finds highlight that the liver has overlapping systems that can trigger regeneration in response to a variety of problems. Yet a third paper, "Caveolin-1 Is Essential for Liver Regeneration," appeared in Science several months later (2006;313:1628-1632), which does not reference either of the above studies.

It's much the same story of hormonal control of the growth of other glands, such as the adrenal cortex and thyroid, and control of ovarian follicle and sperm development. But there apparently has been little or no further study of negative feedback control of adult size of liver and other body parts, as in our growth control theory (but see below on such control of the size of the cerebral cortex).

Only recently have the probable inhibitors, upon whose action the model is based, come to light. These are the small inhibitory RNAs (ribonucleic acids), ranging in length from 21 to 28 nucleotides. They regulate gene expression by repressing translation of target RNAs and also destabilizing them. Double-stranded RNA, with a single strand kinked back in a hairpin bend, putting two complementary sequences along side each other, very effectively inhibits the genes that participate in the original generation of the RNA, itself. RNA interference also effectively controls the form of chromatin ("building blocks" of chromosomes), which can permanently shut down or delete sections of DNA (desoxyribonucleic acid). Other candidates are "antisense" RNAs. Thus, quoting Wayt Gibbs in "The Unseen Genome" (Scientific American, Nov., 2003, pp.46-53).

When the gene is producing a sensible RNA message, its alter ego can churn out an "antisense" RNA that has a complementary sequence. Whenever matched sense and antisense RNAs meet, they mesh to form their own double-stranded ladders-effectively interfering with the gene's ability to express its protein....at least 1,600 human genes (and probably many more) have a mate that yields antisense RNAs."

A negative feedback mechanism for control of the growth of the cerebral cortex has come to my attention (March, 2006). An article titled, "αE-Catenin Controls Cerebral Cortical Size by Regulating the Hedgehog Signaling Pathway," by Lien et al. recently appeared in Science (2006;311:1609-1612). Its Abstract reads as follows.

During development, cells monitor and adjust their rates of accumulation to produce organs of predetermined size. We show here that central nervous system-specific deletion of the essential adherens junction gene, αE-Catenin, causes abnormal activation of the hedgehog pathway, resulting in shortening of the cell cycle, decreases apoptosis, and cortical hypoplasia. We propose that αE-Catenin connects cell density-dependent adherens junctions with the developmental hedgehog pathway and that this connection may provide a negative feedback loop controlling the size of developing cerebral cortex.

Aside from the negative feedback aspect, this is not the type of control proposed above by the Weiss-Kavanau model. The authors, however, give no background or general discussion of negative feedback control of other organs or structures.

The next item of interest concerning liver growth and regeneration appeared in Nature (2007;445: 886-891) the following February, and another in Science (2007;315:1853-1856) in March, neither with any mention of negative feedback control. In view of the above, there appears to have been a 'disconnect' between recognition in 1957 that the dynamics of liver regeneration was consistent with negative feedback control, and subsequent related studies. This can be partly rationalized by the following observations from another 2007 article, "Multiscale Modeling in Biology," in the Amer. Scientist (95:134-142), by Santiago Schnell, Ramon Grima and Philip K. Maini.

Firmly rooted in observation and experiment, biology for decades had little use for mathematical modeling, which was, in any event, a slow business until computers made it possible to simulate large complex systems of nonlinear equations. Today biologists and mathematician desperately need each other -- not just to find structure in the vast quantities of data flowing from experiments but also to integrate this information.....The field of mathematical biology can finally, with the turn of the century, be said to have matured.....It is an exciting time to be a mathematical biologist, or a practitioner of systems biology, as the reborn field has come to be known....."to think is to model".....today no aspect of biology can afford to disregard quantitative measurement and analysis as too boring, time consuming or difficult.

I suggest that Weiss was decades 'before his time' in deciding to have me formalize and analyze his compensatory growth model in mathematical form.

One of the highlights of my stay at Rockefeller was attendance at a lecture by Prof. D.W. Wooley. He had done pioneer work on the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)], and its importance in various physiological processes. Yet, he was unable, at first, to get it published. The Journal of Experimental Medicine, redacted and published at his home institution, the Rockefeller Institute, rejected it in the 1950s, forcing him to go elsewhere. You can't read papers about the workings of the brain today without repeated mention of serotonin. It is causally involved in multiple central nervous facets of mood control, and in regulating sleep, anxiety, alcoholism, drug abuse, food intake and sexual behavior. In peripheral tissues it regulates vascular tone, gut motility, primary hemostasis, and cell-mediated immune responses. There was Wooley, totally blind, seemingly enjoying rubbing it in to the very Editorial Board Members who had turned his paper down two or three years earlier.

Two workers in Weiss' laboratory at the time were Dr. Aron Moscona, about whom more below, and Prof. John Randall, on a fellowship from King's College, London, where he headed the Medical Research Council's Biophysics Research Unit. During World War II, at Birmingham University, he had developed the "war-winning cavity magnetron," which I encountered frequently in my subsequent excess property acquisitions at UCLA (see Chaps. 7 & 9). I had dinner with him and his wife on one occasion, and heard much of his impressions of Weiss' laboratory. Randall is in the news these days (2006) in connection with his mentorship or supervisory capacity over Maurice Wilkins and Rosalind Franklin in his Research Unit, the former of whom shared the Nobel Prize for Physiology or Medicine in 1962 with Watson and Crick. Franklin's x-ray crystallographic images were keys to unraveling the structure of DNA by Watson and Crick, but she died before the prize was awarded and could not share in it.

The anharmonic laboratory shaker
The other, minor projects I carried out for Weiss were not of particular note. On the other hand, another avenue opened at Rockefeller that had great future implications for me, eventually resulting in three books in a new field of geometry, namely, analytical symmetry. I named this "Structural Equation Geometry," because its equations were "structure rules" (describing the structures of curves) rather than "construction rules" (describing how to plot curves) like conventional equations.

At Rockefeller, I met a very talented Swedish machinist and engineer, Nils Jernberg, head of the Instrumentation Facility, with whom I subsequently collaborated privately on several commercial ventures. One of these was initiated by a discussion with Dr. Moscona, mentioned above, who eventually joined the Biology Faculty at the U. of Chicago, and with whom I remained in contact for many years.

Moscona described the limitations of the laboratory shakers then on the market. All utilized simple harmonic rotary or linear motion (acceleration proportional to displacement, as with a swinging pendulum), achieved with rotating wheels that displaced drive-shafts and attached shaker platforms. With such motions, cells tended to clump, as standing waves were generated by the solely repetitious motion. When Moscona heard that Jernberg and I were working together, he asked if we could design a shaker without such limitations. It was relatively easy for me to figure out how to convert a standard harmonic motion generator to an anharmonic one (acceleration not proportional to displacement).

For the sake of simplicity, I'll first describe a drive mechanism only for linear simple harmonic motion (for rotary harmonic motion a second drive shaft at 90° to the first is used). For the linear motion, a wheel, that is, a round gear, is rotated about its center. A shaft then is attached at one point of the wheel, at any off-center location, by means of a rotatable pin or bearing. As the wheel is rotated, the shaft is pulled back and forth in linear motion through a ball bushing, just as is familiar from the wheels and shafts of old railway steam locomotives. If the shaft is attached to a suitably-mounted shaker platform with a bearing or pin, the platform will be driven back and forth by the shaft, with what is essentially simple linear harmonic motion.

However, if the wheel is rotated about any other point than its center, with the shaft being driven back and forth in linear motion within a ball bushing, and its end constrained to follow the wheel's periphery, linear anharmonic motion is obtained. With suitable coupling arrangements, a second shaft at a right angle to the first also can be attached to the platform. One shaft then will drive the platform back and forth, while the other, at the same time, drives it from side to side. The combination imparts anharmonic 'rotary' (also designated "gyrotary" and "gyrorotary") or two-dimensional motion to the platform. This two-dimensional system is not complicated in theory, but is very complicated in practice.

The first problem was with the shaker platform. To work properly, it had to be amenable to moving back and forth and from side to side, without swiveling or tilting. In other words, it had to be amenable to, say, being grasped by hand and pushed in any direction, but not swivel, rotate in its plane, or tilt from its plane. Such a support for a platform of any type did not exist. In essence what was needed was the two-dimensional analogue of a universal joint. By analogy, such a joint or joy stick can be pointed in any direction but cannot be twisted.

I shall not waste time describing the construction or mode of achieving the operation of the device we invented because, even with complete, detailed drawings (Fig. 2-2), you would not be able to fathom how it worked. Neither Nils nor I was even sure it would work before we actually built and tested it. While each individual component functioned properly, there was always the question of whether the final assembly would do so. The patent examiner, himself, could not fathom how the assembly worked. For that reason, a patent could not be issued until after I brought a working model to Washington, D.C. and demonstrated it to him, receiving a congratulatory handshake afterwards (Patent #2,996,288 for a "Displaceable Support or Coupling Mechanism Resulting in a Universal Plate," issued to Julian Lee Kavanau and Nils Arthur Jernberg on Aug. 15, 1961).

To save money, as we had other inventions in mind, I studied the art or science of patent applications, and prepared an application myself, but had a patent attorney help with the final draft. For the drawings, however, we needed skilled patent-drafting experience, and sought the help of a professional. [The patent Office did not forget me; on Oct. 21, 1965, Mark Owens, Jr., Patent Administrator, acting for the Board of Patents, sought my comments as to the possible novelty, usefulness, and commercial potential of a "Proportional Electronic Temperature Controller" in private industry. I replied that "the above-named controller has merit, usefulness, and commercial potential....however, I doubt for several reasons that it is patentable."]

The shaker platform, however, was only the beginning of our problems. For one thing, we wanted the shaker to be programmable, that is, we wanted it to provide the option for different types and amplitudes of motions and accelerations, even specific types, on demand. For another, we needed a driving mechanism with two shafts, where one could be readily disengaged, so as to provide either a linear reciprocating motion when disengaged or a rotary-type motion when engaged.

In fact, the driving mechanism was also sufficiently novel to qualify for a patent, itself (Patent #4,214,479 for a "Cam Driven Curve Tracking Apparatus" (Fig. 2-3) issued to me and Nils on Aug. 15, 1980). This also could have been employed as a toy for drawing weird, complex curves. In essence, as modified for the shaker, it consisted of a nylon gear, either round or elliptical, or virtually any other closed shape with a continuous rim. Close to the rim of this gear, at the side, a continuous channel was milled, of the same shape as the gear, to provide a good fit to a ball bearing, which was free to move within it. Two ball bearings sliding in the channel, with shafts attached to them were mounted at right angles in ball bushings, so that each was free to move back and forth on a linear track, independently of the other. These shafts were attached to the universal plate.

The next requirement was to have the gears rotate around any position in their plane, from the center outward toward the channel. With a circular gear, this would then give a different path of motion and acceleration (Fig. 2-4, using a circular gear with shafts at various angles) for every point in the plane of the gear about which the gear was rotated. Similarly for an elliptical gear (Fig. 2-5, for an elliptical gear with shafts at 90°). We rigged a pencil to the shaker plate to draw the curves traced out by the plate's motion. To my surprise, the curves that were drawn were completely new to geometry, as also was the transformation that was producing them. My subsequent studies of this transformation and the other discoveries it led to, occupied several years and three books, and these only scratched the surface. But I am getting ahead of my story.

It is of interest, however, to explore the paths taken by the shaker platform driven by shafts at 90° for points of rotation of the circular gear along a radius (90°curves of Fig. 2-4) and, similarly for an elliptical gear about various interior points (curves of Fig. 2-5). Let us begin with a circular gear of radius, r, rotated about its center. For this position neither ball bearing in the channel moves, so the platform remains stationary and the curve traced out is simply a motionless point (Fig. 2-4, point near 'center' of the four closed curves for 90°). As the point of rotation departs slightly from the gear's center, an almost circular curve is traced. As the departure increases, the curve takes on an increasingly triangular-appearing aspect until, at the greatest feasible interior distance from the center (close to the channel in which the ball bearing rides), the curve looks like a triangle with slightly curved sides and rounded corners ('vertices'). Except for the point obtained by rotating about the center, these curves were previously unknown and are of 6th degree. With a point of rotation at the rim of the circular gear, it would act as a compass, tracing out a circle of radius = 2r (the outer ¼ circle of Fig. 2-4, 90°) .

For an ellipse, using points of rotation located along the major axis, the curve about the center (midpoint) of the axis is a nondescript arc, which is retraced four times per complete gear rotation (Fig. 2-5). Moving out from the center to a point ¼ of the distance to the vertex, a double-looped curve is obtained, looking something like a stingray. At ½ the distance, one obtains a somewhat triangular curve with two convex and one concave sides. Two 'vertices' are rounded, but the other one, opposite the concave side, is a cusp. The arc obtained by rotating about the 'center' is of 4th degree, as also is the curve shown for rotating the gear about a traditional focus. At all other points of rotation along the major and minor axes, the curves obtained are of 16th degree, while the curves obtained for rotating about the vertices are of 8th degree. Curves obtained for rotating about arbitrary points in the plane are of maximum 20th degree, while those for arbitrary points, but also at arbitrary angles between the shafts, are of maximum 32nd degree. Rarely, if ever, have curves of this high degree been dealt with by classic geometers. In fact, I have no knowledge of classical curves of even sixteenth degree.

Again, all of these curves were previously unknown. Of course, I knew nothing of their degrees either, at the time we traced them from the platform movements. Had I known about them, I would have been utterly amazed. The curves, themselves, were amazing enough at the time we obtained them. Who could have guessed that unknown curves would be obtained using simple transformations of conic sections that any schoolboy could have dreamt up, that is, that as yet unknown features were associated with the circle? Some years later I found that unknown features even were associated with a straight line. Technically speaking, these "unknown features" are that the 90° circumpolar transforms of a line about non-incident points in the plane are of 4th degree.

I should also mention that the shaker platform traveled to a minor extent in the 3rd dimension, that is, up and down (but without tilting). As its supports tilted, with off-center motion, but without their changing in length, the platform became lowered, while when they came back to vertical the platform returned to its former height. This third dimension of motion was another of its advantages as a shaker mechanism.

At this juncture, I am going to depart from a chronological order to complete the developments concerning the shaker, before returning to other events that began during my tenure at Rockefeller with Weiss. At the time I left Rockefeller for UCLA, in 1957, Nils and I were planning eventually to open a shop or form a company in Los Angeles, which he would manage. For that reason we were not in a hurry to find a commercial outlet for the shaker we had developed. However, with the passage of time, Nils married and had a family, and we were less certain of our plans. In the eventuality, Nils died in the 1980's at an early age, ending those plans.

Attempts to market the shaker
On one occasion in 1965, I visited commercial exhibits at a meeting of the American Institute of Biological Sciences and looked in on an exhibit of shakers by the New Brunswick Scientific Co, Inc. This company made the very finest commercial shakers, by virtue of their incorporating dynamic balancing in all their products. In other words, their shakers did not vibrate or shake the table or shelf on which they were placed or fastened. Nils and I felt that, if we did let our shaker out for commercial production, it would be to them. The following is some correspondence between me and Mr. David Freedman, President of New Brunswick. Without implying premeditation, in the end he was able to incorporate some of the advantageous features of our shaker into their product line at no cost to them, and without ever producing our shaker. The following is how it came about. Nils and I had too many irons in the fire to keep close tabs on the 'goings on.'

Sept. 3, 1965
From Freedman: Although we feel that our shakers are relatively well designed and fabricated, we are certainly aware that new designs and new ideas are bound to arise. After hearing Mr. Weisman's rather vague description of your shaker I have become most interested in more complete and more detailed information......I am certain that a mutually beneficial arrangement can be made between us, if your shaker is all Mr. Weisman explained it to be.

I would sincerely appreciate receiving whatever information you may have concerning your design to enable us to evaluate it. I look forward to your reply.

Sept. 9, 1965
From me: Our philosophy has been that it is so far ahead of its time that there is no urgency to get it on the market. Our plan has been to market it ourselves someday and we may still do that.. On the other hand, we've been so busy with more pressing matters that we've had little time to devote to seeing it through. Our thoughts are still in the direction of marketing it ourselves but we are not averse to exploring other avenues. I suggest that you obtain a copy of our patent.....This will give you some idea of the lines along which we have worked. In the event that you have a further interest after studying the patent, etc., we can discuss the possibilities of seeing a working model of the shaker itself, etc.

I also included a list of advantages of our shaker over existing equipment, including the following:

The motion is in general anharmonic, not simple harmonic as with other shakers, so that agitation is much increased, qualitatively different, and smaller forces are required......

The motion is programmable by a simple change of Nylon gearwheels... virtually any program of desired motion is possible. The motions and accelerations involved, for example, with circular and elliptical gearwheels are complex and not readily describable in terms of simple or commonplace curves or oscillations.

Agitation is 3-dimensional as opposed to 2-dimensional

Amplitude of motion is continuously adjustable by a simple mechanism.

One can switch from transverse reciprocation to gyrorotary motion as desired by a simple gear shift.

The universal plate itself has very low friction and is completely silent in operation.

By virtue of the special support mechanism of the universal plate, it can bear stacked and acentric loads, making it possible to have side arms which support trays in water baths, etc.

May 16, 1966
From Freedman: Although some months have passed since we last corresponded about the "Anharmonic Shaker." We have not lost interest in this apparatus.

If possible, when you are in the east again, we would be happy to get together with you to discuss the unit.

June 9, 1966
From Freedman: The main points we are concerned with when considering the manufacture of a shaking machine are the weight-carrying capacity and durability under continuous prolonged operation. If the shaker meets these requirements, my interest is certainly increased and I feel the apparatus possibly has a good place in our line......we do have a Western Regional Manager, Mr. R. J. Yannitte, and I am asking him to visit you to look over the machine initially. I would appreciate your demonstrating the unit for Mr. Yannitte.

If Mr. Yannitte's impression is favorable, would you consider shipping the unit to us? We would arrange for crating and shipping, and we do, of course, guarantee all your rights with the unit.

In the meantime I would appreciate your letting me know the load which the unit can handle and as much other information you can give me.

July 21, 1966
From Freedman: Thank you for the courtesy extended to Rudy Yannitte and to me during our recent visit with you.

As you know, I was quite impressed with your anharmonic shaker. My feeling is that we can provide thoroughly competent fabrication and marketing facilities for your unit and establish a mutually beneficial arrangement.

I believe that it is necessary to review our conversation before we formalize a contract. My understanding is that this agreement will basically include the following points.....

Oct. 21, 1966
From Freedman: We are anxious to begin development of a marketable model, and shall look forward to receipt of the prototype, plan, etc.

Dec. 8, 1966
From Freedman: We thought you might like to know that the prototype shaker and patent papers have been received here.

The shaker has been turned over to our Engineering Department where the wheels sometimes grind almost as slowly as the wheels of the gods.....As soon as the formal royalty agreement is complete, we will forward it to you.

April 6, 1967
From Freedman: We have made substantial progress on the shaker, including considerable re-engineering of some phases. It has taken a little longer than expected, but we are pursuing the project vigorously and should have a model on the market soon.

April 25, 1967
From Freedman: We have made a new Shaker which, although still in a rather crude form, we demonstrated at the show [Federation Meeting in Chicago].

We used a modification of the Universal Plate system and an entirely different mechanical system which had incorporated in it a method of counterbalancing the machine in both reciprocating and rotary motions. I think you will find our efforts in this area quite interesting.

At the meeting mentioned, an unknown number of tentative orders were accepted.

June 12, 1967
From Freedman: The attorney has just contacted me concerning the follow-up on the agreement. He recommends that it be concluded and recorded in the U.S. Patent Office. I will appreciate your review so that we can conclude this agreement.

We are progressing nicely on the Shaker, and I will be in touch with you when the machine is ready for your review.

June 15, 1967
From me: Two people from Lab-Line and Scientific Products were here Monday trying to corrupt me on the shaker, but I told them arrangements already had been made with you. [In retrospect, changing affiliations at that time might have led to actual commercial products rather than leading to the long-postponed dead end with New Brunswick]

There intervened here discussions between my bother Dick, representing me and Nils, as our Lawyer, and the lawyer for New Brunswick.

August 5, 1969
From me (over 2 years later): Regards from the west. This is just a very brief note to inquire how matters are proceeding with the shaker. Naturally we've been awaiting word anxiously the past months and hope that you are close to a first production model.

August 29, 1969
From Freedman: By this time you must have wondered what happened to me and your ideas on your shaker. Unfortunately we had run into some little problems on the shaker and were not quite satisfied with the design, after which there seemed to be some delay in working out a final agreement with you, and somehow without my intention the effort on that particular shaker seemed to diminish. It is hard for me to tell why, but probably due to my negligence. Your letter has sort of revived my enthusiasm, and I will be trying to get Engineering on stream again in the next few weeks after the vacation period is finally completed.

Feb. 6, 1970
From Freedman: We have set a priority list of new products to be designed, and your Shaker is nearing the top although it has not quite gotten there yet. It should be only a short time before we move into it....In any case, we hope to be working on your machine in the near future until its completion and it is ready to go. Of course, I will be happy to see you any time that I have my feet on the ground.

March 24, 1971
From Freedman's secretary: Mr. Freedman is on an extended trip abroad and, therefore, it is not possible to reply to your letter of February 20 until after his return sometime during the first week in April.

April 19, 1971
From me: I guess I was in error in assuming that since I hadn't heard from you, you weren't making good progress with the new shaker. Now I see by the March 19 issue of Science that you already have marketed the first model of a combination Gyrorotary and Reciprocating shaker (Fig. 2-6). I'll be looking forward to hearing more about it when you can find time to drop a line to me.

June 11, 1971
From Freedman: Please excuse the very long delay in responding to your first as well as your second letter.

In the last year or two, things in the scientific business have been rather difficult and we have limited the amount of engineering effort being put into equipment. The individual engineer assigned to your shaker had not done what we consider a satisfactory engineering job so that it could be turned out as a commercial product and, therefore, the product was shelved for an extended period of time.

We did get good response and reactions to this combination when we took it to shows. I have had a recent meeting with our people and, although there has been some disagreement as to whether we should proceed and completely redesign some of the design parameters, we do expect to proceed in the near future with additional engineering effort.

The ad you saw in "Science" was merely one of our water bath shakers that showed a reciprocating mechanisms that could be removed and a gyrorotary mechanism substituted and, of course, vice versa [Here it is explained that it's alright to 'appropriate' our idea of "two shakers for the price of one" (by a simple gear shift) because it was achieved by a less ingenious mechanism. This is hardly the "we will, of course, guarantee all your rights with the unit" of the letter of June 9, 1966. JLK]. This does not begin to offer the flexibility that we hoped would be achievable with your design. In any case, if you care to allow us to have a little more time [I'm breaking out in uncontrollable laughter as I read and type this], we expect to proceed with what we hope will be a very good design. If by this time you are disenchanted with the lengthy efforts involved, please feel free to discuss that matter with another manufacturer, but let me know so that we do not start putting in engineering time without your agreement.

It has been some time since I have been to California. However, on my next visit to Los Angeles I fully expect to drop in to see you and discuss these matters personally.

June 18, 1971
From Freedman: I received your letter of June 14 and I will be carefully following up this project from here on in.

I wish to thank you for your patience and general interest.

Although I wrote further letters to Mr. Freedman on Oct. 5, 1972, April 5, 1973, June 30, 1973, June 11, 1974, and another undated one, in which I expressed less patient concerns, I received no further word from him. He did, however, return our original prototype in response to my request in a 6th letter. But we never received back the model of the universal plate that I took to Washington, D.C. to show the patent examiner. I loaned the prototype shaker to one of my students for experiments by his mentor in the Medical School here for some months, but have since passed it on to my son, Christopher when my quarters at UCLA were shrunk to make way for new faculty. Unfortunately, Nils died in the interim, in the 1980s.

The crux of the problems with bringing the shaker to market was the policy of New Brunswick to market no shaker that was not dynamically balanced, and their inability to achieve this with our invention, though they claimed to have done so in the letter of April 25, 1967. Perhaps I should have taken on a greater role in this endeavor, because the problem of dynamically balancing it, presented an almost equal challenge to that of designing the shaker itself.

In my estimation, the most feasible, though perhaps not entirely practical, solution to the problem would have been to mount an identical second shaker with roughly similar loads and identically programmed cam settings, upside down, with opposite orientation, directly under the platform on which the first was attached. That way, all movements and moments of inertia would cancel each other. The platform of the second shaker could be suspended on four arms, so that the second load could stand upright, just as that of the first. Or the second unit could be appropriately mounted upright, side to side or end to end, but that would not compensate for the vertical movements. In any case, there would be an additional torque about the center of mass.

Although Mr. Freedman and New Brunswick never succeeded in achieving a practical solution to the dynamic balancing problem, as noted above, along the way they incorporated other beneficial features of our model into their line, such as switching between reciprocating and rotary motion, mentioned above (and in Fig. 2-6). Incidentally, even without dynamic balancing, our shaker works entirely satisfactorily. Mr. Freedman was a perfectionist. I have our prototype here with me now in my office but am not inclined to pursue a commercial venture with it or the curve drawing apparatus, particularly in view of the ease with which computers can now program laboratory shakers and draw curves.

I'm sure readers will have their own thoughts about the manner in which we pursued trying to commercialize the shaker. I comment only in mentioning again that I had many irons in the fire during those times. In addition to a full load of research and teaching at UCLA, I wrote three books on the physical chemistry of water and structure and function in biological membranes, was engaged with Nils in manufacturing and marketing fluid dispensers, and was pursuing a law suit against the VirTis company, involving several trips to New York, in the matter of royalties on my chamber-type laboratory freeze-dryer, developed during my research in Sweden, and at Rockefeller, about which more below and in Chap. 3

Other commercial ventures
Concerning the fluid dispenser referred to above, I had designed a shelf-mounting unit, the use of which eliminated the need to pour dangerous reagents from bottles into reaction containers. By one-handed operation, eliminating the need for old-style pinchcocks. At the touch of a fingertip or container, drop quantities or continuous flow could be achieved, without losses or contamination (Fig. 2-7). As equal partners, Nils and I contracted out the manufacture of parts, boxes, and printed material to firms in New York City, and assembled and boxed the dispensers ourselves on weekends. Mr. Wechsler and Palo marketed them for us. A letters patent on a "Fluid Dispenser," Serial no. 520469, filed on 1/13/66 eventually was issued Fig. 2-8), with the Notice mailed on 3/28/68.

Intending to have the dispensers manufactured eventually in California, my brother Dick formed a corporation for that purpose with Nils and me as the sole owners. In 1957-1958 ½-page and full-page ads were running in Science. UC Berkeley eventually had over 125 units in use in their student Chemistry labs. We assigned the patent to Biopex, Inc. of Los Angeles, who arranged with Mr. Wechsler's new company, Greiner, Inc., to market the units. However, Biopex was reluctant to advertise in Science because of the expense but, instead, relied on ads in catalogues and house organs. Eventually sales dried up. I was too occupied with other matters to tend to the dispenser further.

Continuing at Rockefeller, and the Weiss Correspondence
After arriving at Rockefeller in 1955, I began to make plans to resume my research on amino acid metabolism during sea urchin development (using new material collected at Woods Hole in the summer of 1956). My previous studies along these lines led to publication of chapters in two books: "Metabolic Patterns in the Sea Urchin Embryo," in Embryonic Nutrition, 1958; and "Biochemical Patterns and Autolytic Artifact," in A Symposium on the Chemical Basis of Development, 1958. To resume these studies, it was necessary to construct and employ another model of my chamber-type freeze-dryer. I had brought two condenser units with me from Sweden, so I needed no glass-blowing assistance. At that time I resumed contact with Mr. Wechsler at Palo about commercializing the freeze-dryer. This eventually led to contacts with the VirTis Company and the episode in my life I refer to in Chap. 3 as "The VirTis Affair."

During my stay at Rockefeller, Weiss had allowed me to spend some time during a summer at the Marine Biological Station at Woods Hole, where I collected and processed the batch of sea urchin embryos mentioned above for further metabolic studies. On one occasion during my stay at Rockefeller I was invited to give a seminar on my studies at Harvard. Only after my arrival did I learn that I was being considered in their candidate search for an embryologist. They made me no offer but I would not have been interested, in any event. For the year 1957-1958, as noted above, I was invited by Henry Allen Moe, secretary of the Foundation, to apply for a Guggenheim Fellowship, but declined the invitation, as I was anxious to return to Los Angeles.

Before closing the topic of my stay at Rockefeller, some words are in order about Weiss, since he was somewhat of a controversial figure. In this connection, Dr, Sabine Brauckmann, an historian of science at Dartmouth subsequently (2002) was busy at work with an extensive biography of Weiss. She had already completed a short report about him, "The Scientific Life of Paul A. Weiss (1898-1989)," for the Rockefeller Archive Center. Of him, she wrote:

Now, after I have worked through the archival material at the RAC, the American Philosophical Society, the University of Chicago, besides many other places, I am still trying to grasp this eminent figure of American developmental and cell biology who opened up many frontiers in biology, into which other biologists then immigrated. In neurobiology Weiss discovered the fasciculation of peripheral nerves (axonal flow). In cell biology he explained the mechanisms of cell contact with immunological and morphological models and coined the term of contact guidance. In October 1960 he and his collaborator Cecil Taylor produced a media event when they announced their data on the self-sorting of cells, demonstrating that cell suspensions have the ability to reconstitute complete body organs, an experimental predecessor of modern stem cell research. During his war research on neurosurgery he developed a new technique for bridging cut nerves without sutures. Modern medical technology utilizes his patent for welded tantalum tubes to pin together broken bones....He proposed to restructure the classical canon of biology and, thus, helped to initiate the new disciplines of developmental biology, cell biology, biophysics, and molecular biology.....he has borne a large share of professional responsibility, having served in editorial capacities on many of the leading biological journals, assumed important roles in the NAS/NRC, the ISCB, was a member of the Club of Rome, and served as an officer of numerous scientific societies, including the Society for Study of Development and Growth, and the International Institute of Embryology. In 1977 Eugene Garfield evaluated the Science Citation Index and listed the 250 most-cited primary authors in the sciences from1961 to 1975. Paul A. Weiss belonged to this list.....it was said that Paul Weiss had no peers.

Weiss had a superb command of the English language. My first knowledge of him came through employment of his 1939 text, "Principles of Development" (of which it was said, by Brauckmann,"it was over ten years until his fellow biologists comprehended this masterpiece of "experimental embryology") in course work at UCLA. This was, indeed, an elegant and highly praised book. When I first came into contact with him, at the Wenner-Gren's Institute, as noted earlier, I regarded him as one of the most respected and influential biologists in the world, and nothing that occurred subsequently changed that view.

As the head of his laboratory at Rockefeller, some regarded him as somewhat haughty and autocratic. Our relationship, however, was very cordial, and I visited him and his wife, Nina, on at least two occasions at their apartment in New York City. My relationship with, and access, to him was somewhat privileged, as I was seeking to bolster regard for one of his most favored theories and projects, that relating to growth and growth control, treated earlier. And my stature with him rose as our project met with increasing success.

His pace of activities throughout the U. S., end even worldwide, is conveyed well by a joke of mine that circulated in the laboratory. Purely hypothetically, it goes as follows: late one afternoon I was presenting my latest calculations for the growth model to Weiss, and the desirability of exploring another avenue, perhaps with a larger or smaller rate constant came up. Thereupon, I suggested that I could get the new result the next morning and bring it to him after lunch, say at 1:00 p.m. To this, Weiss replied, "sorry, I won't be able to make it, I'm chairing a National Research Council Committee meeting in Washington at 1:00 o'clock. But what about 4:00 o'clock?"

At that time, I wrote to UCLA inquiring about the possibilities for a position in the Zoology Dept. The Departmental head at the time, Ted Jahn, whose graduate seminar I had previously attended, invited me out to give a Departmental seminar on my studies of growth and growth control. This was very well received and an offer of an Assistant Professorship ($6,060/annum) followed on July 30, 1957, and was accepted.

After leaving Rockefeller, I kept in correspondence with Weiss for the next 10 years. I give a few excerpts from his letters, more for what they tell about him than about my progress. Quite possibly they are among only a few existing examples of his personal correspondence.

Letter excerpts from Paul Weiss
Dec. 18, 1958. You seem to be hitting your stride in teaching and research quite satisfactorily and my revisiting California has given me renewed appreciation of your bias for the particular ecological niche.....

The laboratory is busier than even and the space limitation is becoming ever more serious with eighteen people around competing for standing room. However, the new Research Building is about ready for occupancy and the resulting reshuffling over in our building is going to relieve the pressure. Even so, we are having a nice harmonious group, the old-timers of which remember you fondly and not only in this season of remembrance.

Sept. 21, 1959. Your continued probing into the predictive value of our formulae for growth and growth control is quite interesting and important and would remain so as a methodological lesson, even if the biological utility should turn out to have been over-estimated. Although I am keenly interested in these sequelae of our work, I certainly could never consent to have my name placed on a paper to the substance of which I have had no direct relation. This is not any sign of lack of confidence in your work, but quite to the contrary, an expression of my esteem for the intellectual as well as factual contribution you have made to this program even in our first paper, let alone in this follow-up.

The laboratory is running smoothly. I have drastically reduced the size of the staff to establish, in terms of our paper, a more favorable ratio between generative and differentiated mass.

Oct. 21, 1959. Our paper has been very much in demand but I have not been able to check the literature for any tangible extensions [I never learned who had requested reprints. JLK].

Oct. 13, 1960. ....I do want to save you further delay of the paper on Growth Control II. I read it on the boat and found it quite good. However, there should be a "summary" of the factual content, which could either replace your "Conclusions" or succeed them.

I should be glad to introduce the paper for publication in the Proc. Nat. Acad. Sci., but must warn you that the charges there would be of the order of $20 per printed page, since I have exhausted my free allowance.

Aug. 8, 1961. ....You must excuse my tardiness. With illness, two trips to Europe, deadlines for submitting applications, manuscripts, and research operations, and some heavy committee work, most recently for the National Resources Survey delegated to the National Academy of Sciences by President Kennedy, I never quite catch up with correspondence or professional writing either, hence even now must be brief.

....Your attempt at encompassing both ends of the biological spectrum, that of molecular biology and behavior, is certainly most praise-worthy and if carried on in a unified mind instead of in schizophrenically separated compartments, is bound to produce intellectual results of hybrid vigor. Whether the degree of sophistication and quantitation in which you indulge is quite justified in this day and age of practically total ignorance about some of the basic parameters of behavior might be questioned by some, but not by me, because I believe that a lot of past work in this area has been futile because of the isolation of individual factors, such as temperature, light, density gradients and what not, instead of studying the proper and unique constellation in which such phenomena occur, since it is constellations to which evolution has adapted organisms rather than to individual components as we single them out in our analytical experiments.

As you see, I have confidence in the validity of your approach even though you obviously travel at your own risk by entering the field without preconceived hypotheses for guidance.

I was glad to see your new contribution to the growth model, but considering the rather specialized nature of this note, would not be surprised if Science were not to accept it [This was the paper on chicken growth (Science 1961;134:1627-1628). JLK ].

Jan. 2, 1962. Your hydrodynamic excursion pleases me very much because it reinforces my own plea for attention to this type of phenomena on the part of biologists. [This refers to the beginnings of my studies on protoplasmic streaming and biological membranes. JLK]

....Because of the undeveloped state of cytophysics and cytodynamics, I should have much rather see you devote your talents to this field than to the more heavily populated, though not less crucial, area of animal behavior. But, then you seem to be making good progress there, too, and so I merely send you my best wishes for continued advances in the new year.

Jan. 16, 1963. Your letter of last summer should have been answered then and there, but European travel followed by a prolonged illness and a strenuous schedule ever since has somehow delayed me to the point where a reply would be quite out of date. I am now looking forward to seeing you at the Princeton meetings and then again at the Ford Symposium in Detroit....

....I am organizing a rather informal workshop at our laboratory in which some of our staff, which now includes also a solid-state physicist, can chew the fat with people from the physical engineering end of the spectrum, Scriven of Minnesota, whom I pointed to your work, will be with us for a whole month, and I intend to invite Kamiya, too....I have been wondering whether it would be possible for you to join the group after the Detroit Symposium and spend perhaps a week down here in various bull sessions....Please think it over and let me have your reply when we meet in Princeton. Best wishes from house to house [I was unable to attend the mentioned workshop. JLK].

Feb. 13, 1963. I have now gone over the outline of your book. Having heard your presentation at Princeton, I appreciate the scope and significance of your task. I was greatly impressed by the broad perspective and disciplined documentation of your theory, and if my encouragement were needed, would give it to you most strongly. I was shocked by the narrow-mindedness exhibited during the conference and the unwillingness of some to open their minds to new suggestions in a field where ignorance reigns supreme. I am not qualified to evaluate the validity of your various arguments and your theory may not hold water at all. But, you should put it to the test by a monographic treatment, which as I understand it your book is contemplating. So, don't let opposition discourage you. Take constructive criticism into account, but don't take opposition into your heart. [In the final analysis, treated below, my main thesis of intramembranous transformations between micellar pillars and discs proved to be incorrect. Nature had found a better solution! JLK]

April 22, 1963. I have received the impressive volume of Developmental Biology dedicated to me on the occasion of my 65th birthday with a deep sense of gratitude and joy. To have been the occasion for such a superb collection of valuable contributions to the field of our mutual allegiance is truly a matter of pardonable pride. I wish to thank you most sincerely for your part in this presentation, and above all, for the sentiments of friendship expressed or implicit in the fact of your participation. They reassure me that the motives underlying my past efforts to strengthen the study and interpretation of developmental biology have not been misinterpreted, even though in the advocacy of the cause I may at times have strained the bonds of personal relations.

May 11, 1964. Thank you for your letter and abstract. The session promises to be a very interesting one. I am looking forward to seeing you in Paris and hearing more about the progress of your thinking on membrane function, which intrigues me very much.

Weiss and I met in Paris at the meetings of the International Organization for Pure and Applied Biophysics. June 22-27, 1964, for which I received a National Research Council travel grant. I delivered the opening paper at the session on "Cellular Contractility and Protoplasmic Movements." My last letter from Weiss was dated May 31, 1967, and pertained to a student of mine, John Morris (see Chap. 9), who had expressed an interest in postdoctoral work in his laboratory.

I never lost my interest in animal behavior studies, and had been in correspondence with Lee Dice at the U. of Michigan, who was retiring and in the process of disposing of his large collection of small mammals to any interested parties in the academic world. On my way to Los Angeles and UCLA, after visiting my relatives again in Detroit, I purchased a Plymouth auto from a car-salesman uncle, and visited Dice in Ann Arbor. There I acquired some deer mice from his collection and took them with me to Los Angeles as pets.

UCLA, 1957-1966
Back in Los Angles, I found an apartment in Westwood Village, within walking distance of UCLA, where I kept my mice as pets. At the University, I was assigned a large office with sufficient facilities for my planned studies. My initial teaching assignment was to take over Jahn's course in Cellular Physiology, while he was on sabbatical, as well as to give a course in Invertebrate Embryology. My plan was to continue my sea urchin studies with material collected at Woods Hole, which had been kept deep frozen ever since, and for which I had obtained a grant from the National Science Foundation.

Continued studies of the growth model
My first research project at UCLA was to complete the growth studies begun with Weiss at Rockefeller. These then could be carried out on a punch-card programmed IBM 7090 computer which UCLA acquired shortly after my arrival. This work eventuated in the two papers on normal and compensatory growth referred to by Waterman, mentioned earlier. The first of these, in the Proc. Nat. Acad. Sci. (PNAS) (1960;46:1658-1673), was on compensatory organ growth in the adult, and was introduced by Weiss.

By reason of the explicitness of the model, several possible mechanisms of growth control could be ruled out as unrealistic. The model reproduced a number of observed compensatory growth phenomena, as well as normal growth. It reproduced the spurt of compensatory growth following artificial reduction of mass, either at equilibrium or during the growth phase. It predicted the spontaneous resumption of organ growth observed after plasmapheresis experiments with adult rats, and it predicted the secondary spurt of growth observed after the 1st week or so in partially hepatectomized rats, that is, rats whose liver had been partially removed. It also anticipated that liver cell protein synthesis in the regenerating rat liver will attain its maximum rate before plasma protein synthesis does, and it predicted the decrease in rate of regeneration of organ mass with increasing age.

The 2nd paper, "Predictions of the Growth Model for Normal Chicken Growth," appeared in Science on Aug. 14, 1961 (134:1627-1628). Its predictions for the concentrations of growth-inhibiting substances and their quantitative distribution in the animal were in good agreement with known developmental changes. Its results were used to predict the course of compensatory organ growth in the immature animal. These could be expected to provide more useful reference points for past and future experimentation than do the findings for the adult.

The 3rd and last paper in the series appeared as a book chapter on "Compensatory Organ Growth in the Immature Animal," in Bone Dynamics in 1964. In this paper the complete range of conditions to which the model applies-normal and compensatory organ growth in the embryo, immature animal, and adult-was subjected to detailed scrutiny. A significant facet of its progressive development has been that each broadening of the vista of the model has brought with it the realizations that it is more complex than had been suspected from previous analyses.

In figure Fig. 2-9 from the latter paper an organ's predicted growth curves under certain specific conditions (the case 11C4) are given for successive days after removing 25%, 50%, and 75% of the organ's total mass from a chicken at hatching, at 24 post-hatching days of development, and in the adult. The predicted relative times of overshooting and undershooting of the value of the normal mass at the given number of post-operative days provides a basis for assessing the model's validity under those specific conditions.

In general, it can be said that the complexity of the model is such that it defies reliable predictions and extrapolations on the basis of limited analyses or a priori reasoning. Few general rules for characterizing compensatory organ growth emerge from the complete analysis that do not have exceptions. Accordingly, the analysis may provide a valuable guide to the properties of other biological feedback systems about which little is known and for which mathematical analyses are not yet feasible.

Behavior studies by capacitance sensing
In early 1961, Ken Norris, UCLA's herpetologist and marine mammalogist, and I decided to combine forces in the study and monitoring of small desert reptiles that burrow in sand. Those who are familiar with Norris' renowned work with marine mammals may be surprised to learn that he also was a herpetologist. By means of capacitance changes that detune radio-frequency oscillator grids, with which submerged animals come into contact while burrowing in sand, we were able to monitor their movements (Fig. 2-10). A new dimension of reptilian activity studies became possible using this technique. Some early observations of several reptilian species-lizards and snakes-maintained in darkness in isothermal sand were made. Patterns of behavior during active phases, depth and rate of diving, and duration of quiescent periods were revealed in detail for the first time. These studies led to the paper of the above title (Science 1961;134:730-732).

These techniques were put to use again by Norris and me in 1966, studying the burrowing of the western shovel-nosed snake (Copeia 1966:650-654). This snake often emerges at the same time at night over fairly extensive areas. The time of emergence probably is regulated by a 24-hour rhythm acting together with the temperature of the sand. If the surface sand is too hot, it waits for it to cool. Once emerged the biological clock is reset, so that the snake comes out again roughly 12 hours later. In this way the snake can take advantage of seasonal temperature changes, emerging anytime from afternoon to evening to late night.

Using a buried pressure-sensing cell we found that the downward pressure acting on a snake's back is roughly the same as it would be in a fluid, but that the sideward pressures are much lower. The maximum time the snakes spent under the sand depended roughly on the temperature, decreasing as the temperature increased. Buried snakes were found to breathe by rapid fluttering of the throat into a sand-free cavity beneath an overhanging scale at the front of the head.

A paper on this work was only published in Copeia (1966;4:650-664) with some editorial reluctance by its Herpetological Editor. This is clarified by Norris' illuminating letter to him, excerpts from which are given below, in which he does not give a centimeter of ground. On Norris' copy to me there is a handwritten comment about the two reviewers' provinciality. [A spectacular example of having a monograph become published over the emphatic objection of a reviewer is given in connection with my much later studies of memory and sleep (see Chap. 11) in 1997 (Neuroscience 79:7-44)].

Norris' letter: The manuscript to my paper on Chionactis with Lee Kavanau came today with appended comments. I am not surprised by them and, in fact, while pondering where to send this paper I wondered if the material on the mathematics of sand pressure regimes should appear in Copeia.

Be that as it may, the material is valuable in my estimation since this is the first treatment to my knowledge dealing with the effects of pressure regimes upon fossorial animals living in loose sand or soil. Thus it is worthwhile to present the theoretical basis for other workers, however, perhaps not to those reading Copeia. Hence, I do not wish to remove it from the paper. Further it is not irrelevant to our own experimental data on Chionactis. To give you an example of what I mean, the equations express the relationships between active and passive states of stress in loose soils and sands, and Chionactis (and other burrowers) live in an environment where these pressure relationships determine activity and have directed selection.

The passive state is relevant to the pressure on the leading portions and dorsal surfaces of a moving animal beneath the sand. An animal inducing compaction through it movements is bringing itself into the passive regime, where pressures are much greater than those experienced by an animal able to maintain itself under active state pressures. Shear failure, also predicted by the equations, is regularly produced by snakes moving just beneath the surface and, hence, subject to vastly reduced pressures. The discussion of the hydrostatic paradox is also valid and highly relevant to burrowing animals. In almost all dunes and loose soils, rocks and vegetation produce conditions discussed in the hydrostatic paradox section. This anomaly predicts that pressure will not increase linearly with depth but quickly reach finite limits and, hence, deep pressures in such situations may be much less than in open sands.

The section has been very carefully thought out, gone over in detail and says what we want to say. I say it is one of the most important parts of the paper, and to remove it would be to put most of the paper back to the level of observational natural history instead of providing material allowing prediction of a quantitative sort.

As I said before, however, it may not belong in Copeia, though there has been an increasing amount of functional literature in the journal, a trend which I applaud....

Now, you think all this over, and if your decision is that you and your reviewer still wish to have the material removed as a condition for publication in Copeia I would prefer to send it to a journal more oriented toward this sort of thing [Norris had Ecology or the Biological Bulletin in mind. JLK]. I'll admit that many of our systematist colleagues might find it a bit much, and even I had to work on it pretty hard at first. At any rate, thanks thus far for the comments....

Behavior of small captive mammals
Around 1961, I also became interested in the problem of sleep. Specifically, it was a matter of how much (or how little) sleep I needed in order stay healthy and function normally. I decided to take a small detour from my embryological studies and investigate this matter with my pet deer mice. These studies led to a paper in the J. Appl. Physiol. (1962;17:375-377), "An Improved Method for the Deprivation of Sleep."

In the introduction to this paper, I stated, "[a] method is presented for maintaining animals awake with a minimum amount of injury, stress, and physical exertion....deer mice (photo in Fig. 6-6) have been kept awake for up to 23 hr/day by gentle means....[t]he technique did not lead to noticeable changes in temperament or sustained weight loss. The animals were trained and adapted to the final regime in a series of steps which allowed them time to discover and develop individually-suited methods for reducing muscular activity and getting sleep. Previous studies (with rats and rabbits), though also involving running wheels, were either excessively traumatic or involved falling into water to be kept awake. With these techniques, the animals were highly stressed, becoming more irritable, aggressive, and even intractably vicious.

Without going into details, the significance of my mouse studies was that they demonstrated the high degree of adaptability of the mice to thwarting almost all my attempts to keep them from sleeping. For every gentle artifice I employed to keep them awake, they devised an innovative technique to render it either ineffective or much less effective. For example, as often as a mouse attempting to sleep was carried upward with the slowly-rotating wheel and lost its balance, it retreated to a rearward location, positioned itself on its curled tail, and rested or slept, as it slid on its tail and was carried upward again.

In another tactic, the mouse would jump onto the axle and perch lengthwise on it on all fours, also pressing its body against the side pane. As the axle turned beneath, it adjusted its hold from time to time to maintain its balance. By means of friction with the pane, it succeeded to a degree in maintaining a fixed position and sleeping, with the axle sliding beneath its feet. Sometimes a mouse would perch transversely on the axle facing in the direction of rotation, succeeding to varying degrees in sleeping, as it let the axle slide beneath its feet. At other times a mouse would hang on its abdomen over the turning axle, sleeping with its legs extended downward and outward on both sides, until it had to scramble or jump back up and start over again. Presaging results of later studies, it was found that whenever the wheels were temporarily disconnected for adjustments, and were free-wheeling, the mice usually began to run them with vigor, even though they were sleep-deprived.

With the above examples of the resourcefulness of wild mice before me, I decided to carry out some further experiments to probe the depths of their capabilities. I started with a simple test in a running wheel which rotated freely and which they typically would run all night. Then I instituted a program in which a light was automatically turned on, say, every ten minutes, but could be turned off by pressing a lever that extended into the wheel space. If the mouse did nothing, the light stayed on indefinitely. But if the mouse pressed the switch and turned it off, it automatically went on again at the next programmed 10-minute prompt signal. The result was that as soon as the mouse learned how to turn the light off, it did so at every opportunity within seconds of its coming on.

To conclude that the mice wanted to avoid being in the light, would have been premature, because the same result is obtained with sound. Nor did it mean that the mice wanted to avoid the sound. If the experiment is reversed and light or sound are turned off every 10 minutes, the mice do the opposite thing. They turn the light or sound back on. The more realistic interpretation of these experiments is that the animals find it rewarding to be able to control aspects of their environment. The same results ultimately were obtained with a wheel rotated by a motor whose rotation was started or stopped automatically. If the wheel was stopped, the mice would turn it on and tread in it. Or they would turn it off, if it was turned on automatically. Although running and exercise are in themselves rewarding, when initiated and performed volitionally, they tend to be avoided when the activities are compelled.

At that time, I received an invitation from a person of great influence to present the results of the sleep-deprivation study to the March, 1964 meeting of the Association for the Psychophysiological Study of Sleep (APSS) in Stanford, CA. Little did I realize at the time how significantly the topic of sleep deprivation is taken by sleep researchers. The matter would have hardly merited mention, except that my declining to accept the invitation came back to haunt me 30 years later. It might have had ramifications in 1992, when I made an unrequited request of the same person on a nrelated matter. For various reasons, however, I was unable to accommodate the request. The interest of sleep researchers in the topic is conveyed by the 2nd and 3rd invitations to this meeting, as follows.

On February 10: I was very sorry to receive your negative response with regard to attendance at the Fourth Annual APSS Meeting, particularly because it is closer to you this year than it is likely to be again for some years. The group would be very interested in hearing about your studies of prolonged sleep curtailment in rats [of course, they were not rats, sleep researchers' favorite non-human subjects, but mice], as would I.

I am sending you a program of last year's meeting so that you may get some idea of its nature. I certainly hope you will reconsider. If you have any questions please do not hesitate to write me.

On March 12: I was, of course, terribly disappointed that you will be unable to attend the APSS meetings. And I can well appreciate the reasons for your decision. However, I am going to make one last desperate attempt, so eager am I to hear the details of your work (and I feel I can speak for the group in this). Would you consider flying up here just for the Saturday Morning Session, and making a brief informal presentation with the group of papers on sleep deprivation? I would be happy to pay your expenses and it would only cost you half a day (although the trouble of getting here is not inconsiderable, I realize).

I am enclosing a copy of the program for your information. I hope this continued attempt at persuasion will reflect only my interest in your work and will not seem unduly coercive.

Automatic Multi-Channel Sensing and Recording of Animal Behavior
These observations interested me sufficiently to lead to my transferring interest from sea urchin development to the behavior of small mammals. Further, much more detailed and extensive, studies of automatic sensing and recording of behavior of small mammals, with the above title, appeared the next year in Ecology (1962;43:161-166) (Figs. 2-11 & 2-12). In addition to controlling the ambient illumination, I was able to monitor and record automatically: time, direction, and speed of wheel-running; times of urinating and defecating; times of entering and leaving the nest, and movements in the nest; time and amount of drinking; time spent eating; and time spent in a stationary wheel (see Fig. 1-8, wheel I-R eye). The paper's objectives were summarized verbatim, as follows:

A new approach to the design and use of experimental enclosures for small mammals is presented. The objectives are: (a) to detect and record automatically a broad spectrum of animal activity; (b) to approximate some of the animal's stimuli, outlets for activity and spatial relationships in its habitat, or to make appropriate substitutions; (c) to make possible experiments in which various degrees of control over aspects of the environment can be exerted by the animals; and (d) to permit continuous long-term studies with a minimum of disturbance to the animals.

Early findings with the male deer mouse, Peromyscus maniculatus, show that certain situations or activities that are rewarding when obtained volitionally, lead to aversive reactions when they are imposed arbitrarily. The factor of restriction of an animal's control over the environment is invoked for the first time to account for emotional responses following deprivation. Some experiments on withdrawal of food and of the opportunity to run a wheel are interpreted in this light.

I would not wish to give the impression that my studies in animal behavior were usually welcomed with open arms. The above paper was my first publication on behavior, rather than primarily on techniques, and it met with justified referee opposition. The paper was first rejected by Science in early 1961. The reviewer found it not to be acceptable in the form submitted. The reviewer felt that:

The rest of the paper is a polemic against bad experimentation with which most biologists and psychologists would agree, but is irrelevant to the equipment design preceding it....

To be acceptable, the paper should be amended to include both an adequate description of the physical parameters of the apparatus....and the report of an adequately....described experiment. The obvious dependence of the behavioral data on the physical characteristics of the apparatus need no amplification. And it should be stressed that without the careful reporting of an....experiment the paper describes a curious gadget and simply makes testable but unsubstantiated conjectures about behavioral possibilities.

I should state first, that I almost always welcome referee comments, which infrequently fail to be constructive and beneficial, and sometimes save an author from embarrassment. That was true in this instance also, but the comments were sufficiently negative to discourage me from resubmitting to Science. I decided to revise and make a fresh start with Ecology. My revisions and rewriting of a paper submitted in June of 1961, however, proved to be inadequate. The following are comments from the Zoological Editor and a single referee of Ecology.

From the Zoological Editor: Your MS on the gadget for studying animal behavior has been returned by the referee whose comments I am enclosing. You will note that he feels that the MS requires considerable revision before it can be accepted.

On reading the paper myself I not only agree with the referee but find myself distressed by the anthropomorphism and teleological statements that many ecologists find offensive. Can't you avoid words like "reluctant" and "aversion," or at the very least put quotation marks around them? I would also like to avoid such teleology as the mouse "leaving the nest to excrete."

If you want to revise this along the suggested lines you can take at least 90 days with no danger of losing priority toward publication. Please let me know if you wish to do so....

From the referee: This paper is acceptable for publication in Ecology only if the author agrees to revise it.. The author is to be congratulated for his clever apparatus and his refreshing approach to some important behavioral problems, however the tone and style of this paper is not acceptable for the pages of Ecology....

The author is advised to state the purpose of his apparatus, to adequately describe it, and to present some examples of how it has been used. He may then indicate its value to a few theoretical issues....For a paper primarily presenting new apparatus, the description of it is not sufficient-particularly for its construction in other laboratories....What are the dimensions of the nest and what kind of material is used in its construction? How long will a moist fecal bolus short out the grid? What is the purpose of two solenoids in the food dispenser? The names of manufacturers of any special items would be helpful. Although a full wiring diagram is unnecessary, some references to the electrical programming mechanism should be made. A photograph of the apparatus with actual construction plans would be better than a schematic figure.

Preliminary findings. A thorough description of some of the procedures used and the type of results they provide should be substituted for the anthropomorphisms, expectations, criticisms....

Theoretical implications. Since the paper does make a contribution here, a few brief paragraphs are warranted at the end where they are separate from the design, procedures, and results. If the principal thesis of the animal's control of the environment is properly stated, the implications and applications can be left to the reader with no more than a possible list of them....

These comments were, of course, very helpful and, after thorough revisions, the paper was accepted over a year later on Aug. 16, 1962. A comment is perhaps in order in connection with the complaints about my anthropomorphisms and teleology. Though I doubtless could be faulted at the time, being a newcomer to behavioral studies and exposition, the pendulum now has swung far in the direction of anthropomorphisms, partly owing to my contributions and their ready interpretation. Illustrative of this circumstance, there occurs in a recent issue of Science (2006;312:1734-1738) a News Focus by E. Pennisi titled "Social Animals Prove Their Smarts," in which the comment appears,

What was once considered a sharp line separating humans from all other animals is becoming a blurry gray area, with various animals possessing certain parts of the set of skills that we consider advanced cognition.

In fact, in my subsequent studies of birds, in which I 'lived' with them most of the day, I understood their behavior and mannerisms so well that I could almost 'read their minds.' In the same article cited above there appeared the statement,

There's no question that birds are more intelligent than anyone thought they would be, Tomasello says.

Evidently Tomasello had not read my book, "Lovebirds, Cockatiels, Budgerigars: Behavior and Evolution," in which there appear the statements (pp. 346, 347),

I am hard put to find a substantial basis for concluding that their [Lovebirds'] mental processes, as assessed from their social interactions, differ from those of mammals in any way but degree.....In essence, the evolving brains of birds have been the artists, composers, and architects of these marvelous works. Since we find the works, themselves, to be wondrous -- and they are but samples of the potential output -- must we not hold the corresponding capacity of the avian brain, itself, in even higher esteem?

Continuing on the topic of anthropomorphisms, there appeared later in 2006 an article, "Mirror, Mirror," in American Scientist (Nov.-Dec., 487-489) by Bradshaw and Sapolsky, including:

....what we can infer about humans and animals have changed. Human-to-animal and animal-to-human inferences are legitimately symmetric. A deeper understanding of brain biology has strengthened this sense of equity.....By erasing an implicit separation of human beings from other species, scientists are pressed to address conceptual inconsistencies and perhaps some uncomfortable conclusions."

But more about this topic in Chap. 10. Unfortunately, my complete file of communications to me about the Ecology paper is largely unavailable, as explained in the Preface. Letters from four of the following were not lost by virtue of having been filed under "correspondence."

Excerpts from surviving letters:
....I do want to register in an impressionistic way the great pleasure that one reader has derived from your publications. For you have widened considerably the conceptual framework within which scientists and others are properly and fairly to understand animal life.

For one thing the ingenuity you have displayed in your elaborately equipped enclosures and multi-channel registering devices to monitor feedings, urination, grooming, wheel rotations, etc., etc., makes an impressive display of how to go about observing what the untrimmed and full behavior of an animal really is....I was intrigued by your demonstration of how many rhythmicities in the organism's functioning tend to become synchronized with each other. The psychologist is helped thereby in understanding that the human being has some ability in, e.g., judging the lengths of elapsed time intervals, and is capable of developing skills therein-"time beating mechanisms...."

However, what is particularly exciting, of course, is your demonstrations that the ability of animals to control and make modifications of their environment can profoundly affect their behavior. Somehow this strikes me as a new insight or a new concept of animal life and activity....yet it had escaped me that an animal may truly initiate action. Yes, later Brady's monkeys which learned to avoid shock by pressing a lever at least every 20 seconds were called by him "executive" monkeys; but they were nowhere near your animals in truly executive functioning. Your animals not only initiated acts but reversed acts (controls) initiated by other (human) agents.

I predict that your reports will have a liberalizing effect on comparative psychologists, not to mention workers and thinkers in other fields. But you know all this, of course! [Surely I must have replied to this highly complimentary letter, but I have no record or recollection of it.]

....I want to take this opportunity to complement you on your excellent and highly creative work in this area of research. After reading your article. "Automatic multi-channel sensing and recording of animal behavior," I have been eagerly awaiting further reprints of your work....

....You are quite right that the responses of an animal held in captivity may not at all indicate what the experimenter supposes they indicate. You are to be congratulated on the skill with which you are devising instruments and procedures for testing the numerous factors involved in animal responses.

....Your discussion of the rewarding effects of voluntary activity as opposed to the non-rewarding effects of compulsory activity is extremely interesting.

(The above were from R. H. Bruell, Psychology; L. G. Clemens, Psychology; J. F. Dashiell, Kenan Prof. Emeritus, Psychology; L. R. Dice, Zoology [earlier I heard from a prior Kenan Professor at U. of North Carolina, A. E. Ruark. JLK])

Another venture into the Arts
At about this time Prof. W.H. Thorpe visiting from Cambridge, U.K. arrived at UCLA with his family for 6 months. Included was his daughter, an artist. I volunteered to show her about the Campus and the City. At one point she took out her sketch pad and made a couple of sketches of me. I felt it only right to return the favor, though I had never before sketched a person in my life (but recall my sketchbook of animals and animal parts in the undergraduate Natural History course at UC Berkeley). So I asked for a photo to work from, and shortly produced an, at least recognizable, sketch. That set me to work doing sketches of our past Zoology Department Chairmen (Profs. Loye Miller, Bennet Allen, Boris Krichesky, and Theodore Jahn), which were much improved efforts. Unfortunately, there was once a fire in my office-laboratory, where these sketches were displayed, and they sustained considerable smoke damage. However, I have other representative sketches, some of which are included here (Fig. 2-13). Included are those of a medical illustrator -- from UCLA, a student neighbor, Prof. Thorp's daughter (bottom right), a singer from the Roger Wagner Chorale, a socialite friend of Lana Turner, and an actress from a waiver theater in Beverly Hills, whom I coincidentally crossed paths with in Westwood the night after seeing her performance.