4:00 P.M.

December 18, 1980

One Man's Error...........
Scientific Creativity in the History of Biology

by Charles D. Howell Ph.D.

Assembly Room, A. K. Smiley Public Library

Abstract

The subject is scientific creativity. A number of scientific discoveries in the area of biology are described. They illustrate many different modes of success: serendipity and other modes of change, trial and error, double checking the obvious to find it is not obvious, Correcting of errors impeding enlightenment, following up of analogous situations, et al.

In all discovery an element of testing is involved. Often a false conclusion is so obviously right , that it goes unchecked for generations till a tip-off leads to its testing. Men seeking agents in an expected situation find a reagent of the opposite nature instead. A conclusion reached that by analogy should fit other similar settings, on testing falls to fit and may reveal new conclusions. Often the logical answer fails to work for a crucial bit of the puzzle is in error or  missing. Men may be frustrated till the error is exposed. They may be awed about the beauty of nature, almost to reverence, only to find it commonplace when the missing piece falls into place.

Scientific creativity is an indescribably complex mixture of skepticism, mental preparation, intellectual astuteness, insight, persistence, luck and dedication to rationality.

Biography of the Author

Charles DeWitt Howell Robertson Professor of Biology Emeritus, University of Redlands. Curator of Entomology and Invertebrate Zoology, The San Bernardino County Museum, w.o.p.

Born: Get. 29, 1910, East Bangor, Pa., in the heart of the slate mining area.

Married: June 8, 1935 to Edith N. Volk, in the heart of the Berkshires, Mass.

Home: Brooklyn, N.Y. through high school and college.

Education. Oberlin College, A.B. 1932, mayor work in zoology, chemistry, and psychology.

The Johns Hopkins University, Ph. D. 1937, mayor work in physiology,and genetics and cytology.

University of California, Riverside, 1969-70, Post-doctoral research in entomology.

Vocation: Teaching and research in biological sciences for 45 years in colleges and universities; 25 years at the University of Redlands.

Publications: Original research in the fields of physiology, genetics, embryology,and entomology.

Member of Sigma Xi, Honorary Society for the Advancement of Scientific Research

Fellow of the American Public Health Service.

Member of American Societies of Zoology, Physiology and Entomology, and other scientific societies.

Local activities: Leadership training, Boy Scouts of Amerlca. Past president of the Society of Sigma Xi, Redlands Club. Past president, Redlands Council of churches. Teacher and Deacon, First Baptist Church and United Christian Church (Congregational) of Highland.

Hobbies: Archaeology, Astronomy, Music, Hiking, Nature Study.

One Man's Error...........
Scientific Creativity in the History of Biology

by Charles D. Howell

My subject is human creativity in the biological sciences, disguised behind a nursery rhyme, "One man's meat is another man's poison". Two men perform the same experiment and one fails and the other advances science. One man makes an error, and another uses it as a cue to go on to success. Sometimes accident, sometimes profound analysis explain the difference. Sometimes the most creative thinkers are hampered by misconceptions of their times which they never can overcome.

This paper is not creativity in action, but the pursuit of other minds in their creative endeavors. I have gotten great joy in this pursuit, following the often tortuous paths of grew minds attempting to bridge the gap of the unknown, to untangle the spider web of 1nformat10n and to weave it into a useful cord of knowledge.

I owe this pleasure to four men whom I regard as great teachers, who thrilled me with their exact understanding and their appreciation of our debt to the past. Two were at Oberlin College: Robert Allyn Budington, gentle and artist Professor of Zoology; and Lawrence A. Cole, mind-boggling and stimulating Professor of Psychology. Two were at The Johns Hopkins University: Herbert Spencer Jennings, eminent geneticist and sensitive and kindly teacher; and Phillip Bard, neurophysiologist, and master showman and lecturer. With them began my adventures in the discovery of human creativity in the sciences.

My first account comes from the golden age of American medicine, for the courage and ingenuity of American pioneers always delights me. About one hundred years ago Dr. W1111am Mayo did one of the first successful gallbladder operations on a farm near Rochester, Minnesota. He gained the courage to perform this feat by his fa111 in reasoning from anatomical analogies.

Dr. Mayo earned his living as much as a veterinarian as by being a physician, especially in the earlier days of his career. His intense curiosity made him ask his neighbors to let him dissect every farm animal that died. He sought to learn from every dissection. He discovered that horses, and some other mammals, have no gall bladders. Since Mammals are all much alike, why couldn't a human being also survive minus a gallbladder?

There were practical reasons for his speculations, far he had applied his thinking to relating symptoms of patients to discoveries he had made on human autopsies. He was sure he could diagnose gallstone pains frog other pains, in spite of not having and x-ray machine to verify them. He had a patient who was suffering such pains, and was at the point of preferring death to continued suffering. Dr. Mayo talked over his theory about the non-essentiality of the human gallbladder with her, and she agreed to let him operate on her, and to let Providence determine her fate and that of the doctor's.

Her ample kitchen was converted to an operating room, and her kitchen table into an operating table. The country surgeon, far away from the centers of medicine In London and Paris, removed a gallbladder full of gallstones, and his patient survived to live a painfree life. Repeated precise diagnoses like this, and successful surgery led to the developing of the famous Rochester Mayo Clinic.

Studying comparative anatomy I was thrilled with the successful application of this kind of reasoning. Let me cite another case of its employment.

Something we almost never see today in America is a person with a huge disfiguring goitre. Yet, when I was a child I saw many people in Pennsylvania villages with this affliction, including my own mother. There are many causes of enlarged thyroid glands, but the common one was a lack of iodine in the diet due to local soil deficiencies. Once the cause was removed, could the disfiguring goitres be removed to make the patients look and feel more normal?

To test this, thyroid glands were removed from some laboratory animals. The thyroid could be removed from a dog without dire effects, so why not from a human? This was done in various parts of the world about the same time. In several cases the total thyroid was removed, and the patients succumbed shortly afterwards with symptoms of tetany. This is a violent uncontrolled contraction of muscles. The immediate exchange of this information resulted in the rejection of this operation as a viable surgical procedure.

Physiologists tackled the puzzling question, why was this operation a failure in humans when it was successful on dogs? An integration of knowledge from histology, embryology and physiology led to an explanation of this and to methods of thyroidectomy that would not harm a human patient. The tetany referred to above was due to calcium deficiency in the blood. The regulation of calcium is under the control of the parathyroid glands. These glands develops in the human embryo close to the thyroid, as they do in all mammals. In some species, the parathyroids become completely imbedded in the thyroid tissue, and in others they are wholly or partially separate from the thyroid. Unfortunately, man is a species in which they are commonly imbedded within the thyroid. Today thyroid surgery is done to leave thyroid tissue with the parathyroids intact so that calcium metabolism is not disturbed by the operation.

So we see that the same kind of reasoning cannot be used with impunity in two different situation. Supplementary investigation and testing must be used to support what, without it, lead to erroneous logic. 

The pursuit of pure scientific understanding sometimes leads to unexpected practical discoveries. This happened to Jan McClean. He was a promising young investigator appointed as an assistant to Dr. W. H. Howell who was t ying to understand the theory of the clotting of the blood. McClean was a student in the medical school of The Johns Hopkins University forced to work his way through medical school, as his parents violently opposed his ambition to get sound physiological training before pursuing the profession of surgery. This position was a big jump from some of the less-desirable occupations he had had. Hashed scrubbed decks on boats in the harbor. He had mined gold in Colorado. He had counted blood cells in an infirmary, worked in a museum, in a college recorder's office, and finally  bn a position in research. .

His job was to extract a substance from body tissues of animals that were thought to be factors in the clotting mechanism of blood. One of these was postulated to be in liver tissue. He was extracting the material from liver, and was not having the success he'd hoped for. After a trying day he left the lab without cleaning up. He returned later to the slightly putrid mess of liver extract, but decided to continue using it-- fresh blood was obtained more easily than fresh liver extract.

So he applied the old liver material the fresh blood, set his stop watch and timed the clotting. Well, it didn't clot at first, so he started over again. It still didn't clot. He took time to make some-fresh liver extract, and it worked, but if he let it stand for a time, it totally prevented fresh-blood from clotting. This was not what their experimenting was all about. He communicated his findings to Dr. E. Howell, and with difficulty got him to witness the experiment. A new substance seemed to develop in old preparations as the enzymes of the tissue destroyed the clotting factor. Thus was discovered the important anticoagulant, heparin.

This is not to condone sloppy laboratory technique. These men kept track of what they were doing and had a keen eye for the unexpected. They turned error into success because they had well-prepared minds. But it is the height of serendipity that while looking for a clotting substance they found an anti-clotting substance.

No pursuit of truth follows exactly the path of any other. So do not think that I am describing a model of how to become a scientist. Each pursuit is a unique adventure of its own. Let us drop back a few centuries and look at the discovery of some of the classical great principles of biology. The discovery of oxygen and the discovery that plants produce it in the process of photosynthesis are considered among the greatest concepts in the history Of science. However obvious and simple these ideas seem to us today, their origins were beset by many pitfalls.

One of the potential science laureates of the eighteenth century was Joseph Priestley, a minister of the Gospel, but not an ordinary one. He was a British dissenter who supported the American revolution, which gained him few friends in England. Later on he also supported the French revolution, which earned him positive animosity. When the Bastille fell, riots burst out in England, and rioters burned not only his laboratory, but his church and his home. He escaped in disguise, eventually fleeing to America. He made his home in a village well-known to George Armacost, Carlyle, Pa., the home of Dickinson College. In the college museum many of Priestley's apparatus and inventions are on display today.

Priestley was a keen observer, an ingenious inventor, and a meticulous experimenter. He produced carbon dioxide by pouring acid over chalk. He went further by dissolving the gas in water, producing a sparkling water, like Seltzer water of the great spas of Europe. His friends and scientific colleagues were delighted with this simple discovery and he was awarded the Copley Medal for this in 1773. He discovered and made laughing gas, which has been a useful anesthetic down to the present time. He discovered oxygen, a story we shall relate later. He also discovered that plants revivify air rendered noxious by animal respiration. In addition he was an- inventor. One of his inventions was the compressed air gun. A model of it was taken on the Lewis and Clarke expedition, where it was used to mystify Indians, for it killed a rabbit it was pointed at with neither fire nor smoke nor a visible projectile.

We begin our story in the midst of his work. At this time the phlogiston theory was accepted to explain certain chemical reactions. Priestley, quoting an eminent mineralogist of his day,called it "the greatest discovery that had ever been made in science". It was the first generalization of chemistry and held sway for almost a century. Priestley, being brought up on it could not escape the entanglements of its reasoning. Consider the beautiful transition of a rusty metallic ore into a shiny useful metal. It was like magic, and was carried out by heating the ore (usually an oxide) in the presence of charcoal. The carbon of charcoal combined with the oxygen of the ore, reducing it to metal and forming carbon dioxide. According to the phlogiston theory, the phlogiston of charcoal entered the ore converting it to pure metal. Such was the magic of phlogiston.

When Nature presents man with riddles, she often also provides a single exceptional clue for unraveling them. In this case the clue was cinnabar, the red oxide of mercury. This is the one natural ore that is a pure oxide without traces of carbonate or sulfates in it. Unlike other ores, it does not require charcoal for its reduction, and can be reduced with much less heat than usually is required for reduction. It had always been reduced with charcoal until Bayen, the French chemist, discovered in 1772 he could reduce it by mere application of heat. However a gas was produced in the process and was identified erroneously by him as "fixed air", the eighteenth century name for carbon dioxide. The retesting of this gas was to fool two other eminent experimenters before its correction was to lead to the discovery of oxygen.

Priestley repeated Bayen's experiment, and tested the gas by putting a lighted candle in it. The candle flared up and burned brightly. This was the kind of reaction he had noted when he put a burning candle into laughing gas in 1772. Remember that he had no idea of a gas like oxygen doing this. So naturally he identified the gas as "dephlogisticated nitrous air", his name for laughing gas. In his previous experience this air suffocated mice, but at this time he did not put a mouse in it.

Shortly after this he went to Paris and communicated this experience to Lavoisier the great French Chemist, then merely a young man compared to Priestley. Lavoisier promptly repeated the experiment. He used a test Priestly had invented for the"goodness of air". According to this test he said the gas evolved was common air, but he noted it was "purer than common air". When Priestly read this he was puzzled about the contradiction of his conclusion. Of interest, he later wrote of Lavoisier,"truth has been a means of leading him into error, error may, in its turn lead him into truth." This was to prove very prophetic.

Let us consider Priestley's test for goodness of air. It was really a test for oxygen, but that was not known at the time. If you mix nitrous air (NO or nitric oxide) with half its volume of oxygen it will produce a red gas (N02 or nitrogen dioxide) which will dissolve fully in water leaving no gas behind. If used with air, which is four-fifths nitrogen, the nitrogen is left behind. Priestley had experimented by trial and errand had found that he could get a "maximum reduction" of air if he mixed one part of nitrous air with two parts of common air. This mixture,instead of giving three volumes, gave 1.8 volumes. With impure air he got less of a reduction. Thus the greater the reduction the purer the air.

Since laughing gas is negative to this test, he did not think of using the test on the new gas. But he soon was led to change his mind when he found that the new gas did not dissolve in water, as laughing gas does, no matter how hard or long he shook it. He still had no idea it was common air, but since it might be like it, he decided at last to perform the "goodness of air" test on it. It reacted so much like common air that he was about to give in to Lavoisier's-conclusion. But if it was true, the test must have left behind the suffocating mephitic air (nitrogen) of common air. To prove this, he inserted a burning candle. The candle was not snuffed out, but flared up brightly. It was NOT mephitic air'

How strange. Could an animal live in this air? He inquired if any of his friends had a mouse. Someone did, and Priestley put it in this sample of gas. The mouse survived twice as long as usual. It was not common air, and yet a mouse lived in it. He performed the goodness of air test on the sample the mouse had been in, and it proved to be as good as common air. He repeated the test on this used sample, and again it was reduced. At last he thought of performing a succession of tests of the goodness of air on a given sample of the gas.

The next day he started from scratch with a fresh: sample of the gas (see Figure 2)  He reduced it with nitrous air, and found it reduced slightly more than common air. He repeated this a second time on the once reduced sample, then a third time, and then a fourth , and not till the fifth attempt was the volume increased by adding nitrous air.It was four to five times as pure as common air -a new gas. Priestley called in Dephlogisticated air, but it later came to be known as Oxygen.

Lavoisier picked up the story from here. He oxidized mercury with oxygen, and found the oxide had a greater weight than the original metal. From this he developed the modern concept of chemical reaction, and established the foundation of modern chemistry. From error he went on to truth as Priestley prophetically stated.

Prlestley still believed in the phlogiston theory, but this did not stop him from continuing to make great scientific discoveries. He was puzzled, and wrote, "The quantity of air which even a small flame requires to keep it burning is prodigious. It is generally said, that an ordinary candle consumes...about a gallon a minute. Considering this amazing consumption of air, by fires of all kinds, volcanoes, etc., it becomes a great object of philosophical inquiry to ascertain what provision there is in nature for remedying the injury which the atmosphere receives by this means . " He recognized that without such a provision,"the whole mass of atmosphere would, in time, become unfit for the purpose of animal life." Priestley did not rest on his laurels. He was thinking creatively.

He soon discovered that plants purify air, a tremendous discovery of one of the most beautiful balances in nature. But let us review briefly some of the reasoning, problems, an pitfalls that beset him.

First, like McClean and Howell,he set out with an erroneous hypothesis from which he arrived at the correct one. Be reasoned that since living things, like mice, poisoned the air, then plants should do the same thing. So he grew plants in his bell jars sealed with water, but he didn't do it in a simple-way. First,he let a mouse use up the air in a bell Jar, and then he put a plant in it, expecting it to wilt and die at once- saving time for the experiment. But, the plant did not wilt and die. After it had thrived for several days, he decided to examine the air by putting a mouse back in it. To his astonishment, the mouse survived a long time. The air must have been purified.

Now he reasoned critically. Maybe the air purifies itself on standing over water. Actually it does, but at such a slow rate that he wasn't going to be bothered by it. To test this he took some large quantity of air made noxious by animals living in it till they collapsed. He divided it in two. In one half he put a plant, and he left the other half standing over water with nothing in it. The plant thrived. In fact, it seemed to grow even better than in common air. After about a week he put a mouse in each of these jars. The mouse in the plant side stayed alive instead of collapsing, but the mouse on the other side collapsed at once. So he felt certain that the plant, a bit of mint, had rejuvenated the noxious air produced by animal respiration. Be found that other green plants do this also.

Priestley published these profound   new discoveries, and then abandoned his experiments for a number of years. He was very busy in his pastorate, and could not return to science for five years. When he did, he tried to sandwich his experiments in a busy schedule. Perhaps he did his work chiefly at night, and did not put his plants in a lighted room, but at any rate, he failed to be able to verify his earlier work. The plants did not revivify the air. He had no idea that sunlight lay behind the successful observations he had made before. He thought he had made a mistake and was about to deny the validity of his own work.

But other men had already read the work and had tried to repeat his experiments. One of them saved Priestly the ignominy of saying he had made an error in his meticulous work. This was Jan Ingenhouez, a Dutch botanist. He had discovered that plants perform this wonderful function of purling air only when in the light. So sunlight was brought logo the story, and piece by piece the great Canvas of scientific understanding had another masterpiece painted in. 

Scientific conceptualization does not progress so much by destroying the past and rendering it obsolete, as by adding to, mending and patching its past concepts. Let me cite one simple example of the mending of a great concept, in the present century.

The importance of sugar as a source of energy developed during the late 19th century. for about seventy years the idea that muscular work derived its energy from the oxidation of glucose held sway. In 1933 is was conclusively proven that muscles could perform to their full strength in the total absence of the:oxidation of glucose. The source of muscle energy Was a newly discovered type of chemical reaction, the breakdown of an organic triphosphate into a dlphosphate. The loss of one phosphate released energy to the muscle, not the oxidation of glucose.

This new concept did not utterly destroy our faith in glucose. It was not faith, but knowledge we had about it. That knowledge was now revised as we found glucose still held a place of mighty power. It is the source of the energy that builds up the triph phate. This debunks eating a sugar cube for quick energy.

So science builds most firmly by addition and correction. -As a corollary I might add, if you see anyone trying to totally destroy a great scientific concept, rather than trying to amend or improve it, something may be wrong in this person's approach.

The unraveling of the mystery of the chemical-physical nature of the gene also illustrates this gradual process. When I wee in graduate school the status of proteins wee quite sacred. They make up the warf and woof of biological matter. We knew of nucleic acids, but they weren't in any beginning texts. We believed the gene had to be a protein, and if nucleic acids were terribly prominent in gene material,the gene must be a nucleoprotein.

Did you, as a child, ever fold paper in many ways and cut off Corners and then unfold the paper to see what kind of beautiful pattern you had created: Well we did this seriously in graduate school, searching by trial and error to find a new pattern into which the structures of the parts of nucleoproteins would fit. We all hoped for a nightmare like Beetle got revealing the structure of the benzene ring. But no one got such a vision.

One set of facts we had to fit into the story was the fact, well known in 1930, that the number of molecules of a purine, which I will call "if' was equal in the gene, to the number of molecules of a pyrimidine I shall call T''. Also the molecules of "G" another pyrimidine equaled those of "C", another pyrimidine. This seemed to be a universal law in all genes. Why? or How7 How could a molecule be made to fit these facts?

We did not have the tools of Xray diffraction studies, nor know how to measure the angles of chemical bonds, nor the length or energy of bonds then as could be done by the 50's. But these and more ideas were available to James D. Watson and Francis Crick in 1953 when they solved the riddle.

Watson was a very young postgraduate student, 23 years old, when he went to study in the famous Cavendish Laboratory in England. Of interest to our account is the fact that Cavendish wee one of the last great Chemists to uphold the Phlogiston Theory, in spite of discovering hydrogen and showing the molecular structure of water was H₂O.

Watson was driven by an almost fanatical urge to beat the twice Nobel Laureate,Linus Pauling,to the discovery of the chemistry of the gene, by fair means or foul. He became associated with the brilliant physicist, Francis Crick, and the two worked hand in hand from there on. They had three-dimensional metal models made to-scale, of all the parts of the nucleic acid molecule, and tried to fit them into a coherent scheme.

The irrepressible Watson pried into all the laboratories where welcome or not, hunting for a hidden clue. One day, while expounding his vast knowledge of chemistry of purines and pyrimidines, he was politely interrupted by his host, Jerry Donohue. Jerry was a crystallographer with his feet soundly on the ground in a field far removed from the biologists pursuit. Elegantly rebuked Watson for he assurance, and told him textbooks had for years published strictly bogus pictures of the chemistry of these substances. Their real structure he said, was an alternate form never shown in textbooks. It was a keto rather than an enol that. should terminate their molecules.

The embarrassed Watson took it all in, and went home and began cutting out paper models of keto-ended purines and pyrimidines. As Crick walked in on him he had just discovered that the new model of "A" fitted perfectly into "I" in a certain orientation. He at once twisted and turned and inverted "G" and "C" and found they too could f it perfectly. In a short time Watson and Crick had substantially conceived of the double-helix form of DNA. But it took a long time to measure lengths of bond, and angles of bonds and to make new three-dimensional metal models to verify it.

When it was finished, all parts fitted with unbelievable precision. Old ideas and new Smashed , and just at a time when Watson was about to throw out the theory that A=T and G=C. It was true after all, and now they knew why. They had no doubt that this would earn a Nobel Laureate, and it did nine years later in 1962.

Pasteur wrote, Chance favors the prepared minds. The men we have mentioned were not only prepared, they were tenacious and zealous in their pursuit of ideas. They left no stones unturned to resolve contradictions, to make reason work. They devised elegant experiments, made ingenious apparatuses, used logic, trial and error or whatever the human mind could utilize, not being too proud to grasp at the straws of chance and serendipity. After preparation they had dedication.

Scientists. make errors. But Science has no dogmatics holding to them. Science can and does correct itself relentlessly as it advances its understanding of the physical universe. Science exposes the many-sided nature of creativity. "God created man in his own image" it says in Genesis 2:27. I have always doubted that this meant that Man looks like God, but I feel man is nearest God when he is most creative. 

Figure 1 shows how Priestley applied nitrous air to common air. By trial and error he had found he could get the greatest reduction of volume of common air when mixed with one-half its volume of nitrous air.

Because of the solubility of nitrogen dioxide in water it practically disappears, its red fumes dissolving in the water.

Instead of three volumes resulting from his mixture, only 1.8 volumes remains.

Figure 2 shows his application of the same test to oxygen. One volume of oxygen reacts with two of nitrous air (NO, or nitric oxide). Only one quarter of the oxygen is used up in the first test, in successive tests it is all used up by the fourth test. The fifth test would result in a full volumes of NO remaining.

Residual gases escaping out of water into the chamber, including nitrogen and carbon dioxide, and of course the rare gases xenon and krypton, left a small volume behind, so the theoretical situation in not quite realized.