Cancer Pain Reduced Through His Research

Dr. Lyndon F. Small '20, One of America's Top Chemists and an International Expert on Narcotics, Finds Better Drug than Morphine

MEDICAL BOOKS, filled with pictures of terrible diseases, probably can furnish, descriptions of a dozen more dreadful than cancer. But most persons would name cancer as the disease which scares them most. The insidious manner in which it may begin, unseen and unfelt until perhaps too late, makes them apprehensive. When they think of how, despite radium and surgery, it can kill but often not quickly, they are frightened. Faced with cancer, some of the strongest men and most courageous women lose their nerve, like children in the dark. Doctors never told Babe Ruth what was wrong with him.

People dread cancer less as a killer than as a crippler and less as a crippler than as a torturer. Few maniacal sadists who during inquisitions have specialized in engines of pain have shown the imagination which perverse nature has when cancer runs riot in organs exquisitely sensitive.

Morphine helps, up to a point, but it furnishes relief only for limited periods. Many, painfully allergic to it, become nauseated. The more it is used, the less effective it becomes. A cancer patient may end by being forced to endure the agony that morphine can no longer stop and to experience the additional distress of addiction to a drug that weakens the will to endure and ruins the nervous system.

The picture is grim, but it is less grim than it used to be. A Dartmouth man, Dr. Small, has made cancer agony bearable. After life-long efforts in chemical research, he has discovered a drug better than morphine because it is not habit forming and does not cause nausea and other pernicious side effects. Without any appreciable increase in dosage, it retains its full effect.

Since 1939, Dr. Lyndon F. Small '20 has held the position of Head Chemist, Division of Chemotherapy, National Institute of Health, U. S. Public Health Service, Washington. His hair and coloring have led his friends to call him Red.

Because he has given peace to cancer sufferers in their last days, he has a nationwide reputation as a top-notch chemist who is also a great benefactor. His new drug, called Metopon, is also valuable because patients can administer it themselves simply by swallowing it, a method as effective as injection. In these days of overcrowded and expensive hospitals and of too few nurses, many are consoled by the assurance that they can rely on their own hands to give themselves relief from the pains that used to be unbearable and yet too often had to be borne.

Metopon is easy to say, but it was difficult to discover; to determine its effectiveness was still more difficult. A specialist in narcotics, Dr. Small has been trying to find the ideal substitute for morphine and opium derivatives ever since he got with the help of Prof. James B. Conant, now President of Harvard University, a Sheldon Travelling Fellowship to study for a couple of years in Munich under Professor Wieland. That was 22 years ago. In those days the Germans had a world-wide reputation for their scientific industry, perception, and creativeness. Dr. Wieland rushed up one day to Professor E. B. Hartshorn, a Dartmouth professor of Chemistry, with an enthusiasm for an American research student as genuine as it was rare. "Ach, you come from Dartmouth. Small is an excellent chemist."

Dr. Small is now nationally, indeed internationally, known. So varied and complicated is his work that he cannot do it single handed. He has about 20 expert chemists testing the efficacy of Metopon on cancer sufferers and drug addicts.

"The whole problem is infinitely complex," Dr. Small remarks warily. "There is no simple answer. Frankly, we chemists do not know just how valuable a drug Metopon is. In Pondville Hospital connected with the Massachusetts General, we have experimented with patients bedridden with cancer facing extreme suffering and death. We know that they are incurable; we know that they would have to take morphine in ever-increasing quantities; we know that after a few weeks they would surely become drug addicts."

In addition, he has made tests on persons hopelessly addicted to drugs and consequently confined to institutions. He has had cooperation from a hospital in Lexington, Kentucky, for some ten years in administering Metopon to see whether it could help persons break the morphine habit.

He says guardedly that the results so far are "encouraging." "Metopon is twice as effective as morphine," he estimates. "The doses do not have to be increased nearly so much as when morphine is given. It is not habit forming. It has effects like those of morphine, but patients do not suffer from nausea, which is often one of the unpleasant aftermaths of morphine, or from constipation so extreme that it too is to be dreaded. So even if it is not a big item in the history of world medicines it is still worthwhile."

Three companies are now manufacturing this drug; and doctors, except in very backward communities, are familiar with it because articles describing it have appeared in the Journal of the American Medical Association and in state medical journals.

Metopon is about three times as expensive as morphine because it is difficult to manufacture, but the increased cost does not take it out of the hands of poor people. The difference in manufacturing costs based on a day's dose is about 15 cents as opposed to five.

Metopon should not be confused with Methadon, the German synthetic drug designed to relieve pain and help narcotic addicts. According to Life, which had a feature article with pictures in a recent issue, American medical men discovered the secret of Methadon after World War II in the files of a large German chemical firm. Experiments indicate that though Methadon is easy to manufacture, stronger than morphine, and better than some other narcotics in reducing the feeling of pain, it is habit forming, lacks sedative and calming action, and causes dizziness and nausea.

When the Allies betrayed Czechoslovakia and Hitler marched in, Dr. Small and his associates turned away temporarily from a study of cancer and Metopon and began to work intensively on malaria and an effective drug for use in the treatment of that disease. War between the United States and Germany allied with Japan being foreseen even in 1939, he and his chemists began experimenting in the hope of finding something more effective and less harmful than quinine and atabrin. They started alone, but after war was declared, the National Re-earch Council was called in to help coordinate their efforts.

"Malaria was considered the number one problem of the army," Dr. Small observes, "and 16 universities and five industrial laboratories engaged in cooperative research. We turned out the drugs and arranged for places to test them, including half a dozen prisons, where prisoners volunteered as human guinea pigs. In return for money and for time off their sentences, they allowed themselves to be infected with malaria and were given drugs, the effects of which were studied by specialists."

Dr. Small has been told that the cooperative work done by chemists, doctors, and pharmaceutical laboratories on a nation-wide basis to discover a cure for malaria was the second best cooperative effort of World War II second only to that done on the discovery and development of the atomic bomb. Though quinine and atabrin have now been supplanted by new and better medicine, the problem of malaria still remains in the sense that the disease is still very much with us; it can be controlled only after it has developed.

"We are still continuing work in the hope of an ultimate solution," says Dr. Small, though now that the pressure of actual war is off, he and his staff of scientists have returned with alacrity to his early quest, the search for a substitute for morphine.

He was glad 'to get going again, for during the war a German discovered a drug called amadone, a narcotic for the relief of pain supposedly as effective as morphine. He could not rest easy until he had tested this to his satisfaction and learned that it was dangerous, for it had insidious side effects such as violent nausea. He discovered also that drug addicts could use it and actually preferred it to morphine, so obviously the problem was wide open again, at least so far as amadone was concerned.

"Wide open" may not be the right phrase, however, since Dr. Small's patent for Metopon goes back to 1936. The outlook then was good for testing and perfecting his drug, but the war came along, and it began to be distributed illegally with highly unsatisfactory results.

As research chemist, Dr. Small considers himself no sociologist, no philosopher, and no moralist. When he went to the League of Nations Narcotic Conference held in Geneva in 1931, he showed little interest in how much opium was produced for addicts, where it was grown, or in how much was produced for medical purposes or for the black market. He went to Geneva simply as a technical expert for the American delegation to advise what drugs should be controlled and how strictly they should be controlled. With some dismay he noted that only the United States had a qualified expert present who knew what was going on.

Fifty-seven nations signed the treaty, supposedly written scientifically, which had, however, some weasel words that had to be carefully scrutinized. "It was none- theless worthwhile," Dr. Small believes, "and no nation welshed on it, not even Germany in her vilest days. Indeed, the League of Nations' most enduring bene- fits lie in its health organizations working in the field of narcotic control."

Nor is such activity over and done with. There was constant effort carrying over from the League of Nations to the United Nations to which Dr. Small is adviser con- cerning matters in his special fields of drug control.

He crossed the Atlantic for a second opium conference held in London in 1937. This time the League of Nations was attempting to unify criteria evaluating morphine and codeine. The sole purpose of this conference was to attempt to get all nations to use the same standards for its needs and imports. The point is that if one nation uses a different method of extracting morphine from 100 tons of opium, it may get more morphine than is permitted by the League of Nations for importation.

"The Conference was a complete flop," Dr. Small remarks dryly, "for Hitler got loose and everyone lost interest in morphine."

Accordingly he went to Holland and revisited Germany and saw the Nazi Brown Shirts in action. Even in October 1948 he is still amazed that we in America could not foresee what such a gang of ruffians wanted to do to Germany and to the world. He shakes his head still in amazement.

Asked what he did when the Nazi salute was called for, he grins with genuine satisfaction. "Every time a Nazi said HeilHitler and gave the Nazi salute, I did also. I said loudly and clearly as I raised my arm stiffly and defiantly, 'Nuts, Hitler!' I did it all over Germany. I did it on all occasions. I loved doing it. And the Nazis loved it too. It sounded perfect to them. I was happy; they were happy. I really consider this the best piece of diplomacy of my entire life."

WHEN Red Small was an undergraduate at Dartmouth few classmates would have guessed that he was going to become one of the top chemists in the country. They would have bet on a distinguished career in forestry or in exploration. Now 28 years out of college, Dr. Small himself wonders that his passion for the Outing Club did not lead to an early death in blizzards on mountains.

"I remember that Ken Emory he was from Hawaii; it's warm there and I went to Agassiz Basin and over to Glencliff during some terrifically cold weather. I noticed first that Ken's nose was white. It was frozen. Then his feet numbed up. What could we do? We finally ended up in the Poorhouse. It was better there than freezing to death on the mountains, but all we had to eat was some sour milk offered us in a bowl. We did have some bananas with us, but some poor kids who had never eaten a banana fastened their eyes on them, so they got them."

Dr. Small shakes his head in pleased bewilderment at the thought of what he could get along on then compared to now.

"Those were really the virile days," he says. "The way we used to get frostbitten on those damned mountains! No wonder men of my generation say that Dartmouth has gone to the dogs with ski tows and all the modern winter sports luxuries. Well, that's the way every older generation views life, isn't it?"

Asked about how hard he studied at Dartmouth, Dr.' Small chuckles with satisfaction. "Study? I never killed myself. But I was a junior Phi Bete. Well, I suppose that you might say that when I studied, I really concentrated. Then I would head for the hills or for supper in a D. O. C. cabin cooked by Doc Griggs." He doubts that he spent more than one week end in Hanover during his junior and senior years. In those days before ski tows Red Small as a sophomore competed against 40 undergraduates in a competition for hiking the greatest number of miles over D.O.C. trails in one year. Such long distance treks used to arouse great interest and carried considerable prestige. Red won by chalking up miles. His extraordinary speed and endurance over steep grades like Fat Man's Hell and Hell's Highway are still a legend in Robinson Hall.

One of his pet undergraduate gripes was the rule forcing all students to buy season football tickets. "What did I want with them?" he asks rhetorically. "I had better things to do with my money. I wanted to buy cans of baked beans, coffee, and bacon for my Outing Club cabin trips." He recalls that he used to get along beautifully in Hanover on $600 a year, including tuition.

Standing high in science at Dartmouth, Red Small nevertheless liked English and took all the courses in it he could get. Nor did he shy away from languages. He took both French and German.

"Dr. Bolser told me to take German, and so I took it. He told me to learn it well, and so I did."

The German stood him in good stead, for when he got to Munich, he had a solid foundation. By cutting himself off from all Americans and moving only in German circles, he thought and even dreamed in German long before his two years were over. So well had he mastered the language that he could use it effectively in scientific discussions.

During World War I, Red spent some time in the Coast Artillery. Ungiven to superlatives, he says, "The Coast Guard was the most horrible experience of my life. I hated top sergeants and I hated fatigue duty and I hated K.P., where I spent more time than any other man in the service. The happiest moment of my life was when I was discharged from the Service. Really, I mean that. I can still rebor was like, where I stood all night, guarding some gun emplacements which were ready to fall apart."

After being graduated from Dartmouth, Red Small went to Harvard University on the Henry Elijah Parker Fellowship. He did his M.A. thesis under E. P. Ivohler on a "trivial" problem which was not even worth publishing. It was trivial in that he had his eye on his Ph.D. and was working to get off his requirements in a plan that made his M.A. merely incidental.

After teaching Inorganic Chemistry at Massachusetts Institute of Technology for a year, Red Small returned to Harvard on a teaching fellowship, which gave him half his time for the classroom and the other half for work with Professor Conant. He knew John Woodhouse '21, the present Technical Director of the Grasselli Chemical Department of E. I. du Pont de Nemours and Company, better at Harvard than he did at Dartmouth. In the final year at Harvard Red became a Du Pont Fellow with full time for research with Dr. Conant on Organic Free Radicals.

"We turned out several pretty good papers on the subject," is Dr. Small s present estimate.

He has a way of recalling his life as much through his mountain adventures as through his work in research. He had when at Harvard what he is pleased to call "an Historic Time" when he and his wife on snowshoes with home-made creepers climbed hom the Ravine House up to Madison on the Airline Trail.

"It was abysmally cold. This time I was really worried about the outcome. You see, I was the man in the party and supposed to be responsible."

Mrs. Small and he fell in with a group of Russians from M.I.T. on top of Mt. Washington, and they were fascinated because the Russians' total climbing equipment consisted of ten or twelve pairs of pajamas worn simultaneously.

"These Russians seeing an American stove for the first time caught on how to use it," Dr. Small recalls, "but they were a little uncertain about the best methods of getting results. They had built a brisk fire in the oven, and, despite a certain amount of what I thought was logic and experience back of me, I had some difficulty in persuading them to build it where we, perhaps narrowmindedly, always build it."

After a miserably cold night, Dr. and Mrs. Small trekked across the range, but the snow was wrong for snowshoes and wrong for creepers. So they slid down the railroad mostly on their rear ends and found a caretaker named John, who had one scraggly tooth. With pride he showed to Mrs. Small a wildcat he had killed. Dinner consisted of the first deer's heart that Dr. Small had ever eaten. John offered the Smalls a drink.

"It's wonderful stuff," John said modestly. "I made it myself." Feeling less experimental than usual, the Smalls managed to pour most of it surreptitiously out of the window.

Until 1926, to stretch their inadequate income, Red and Mrs. Small took lucrative, enjoyable, and healthy summer jobs, teaching swimming first at Camp Serana on Lake Tarleton and at Aloha on Fairlee in Vermont and later in West Virginia. One of his girls was Joan Bennett, now wife of the movie producer, Walter Winger '15, and another Margaret Sullavan, his favorite, "one of the swellest kids I ever met. really the works." Red had picked up the Australian crawl during his college days from his Hawaiian friend, Ken Emory, now an authority on Polynesia. £0 much does Red still enjoy swimming that one of the high points of his 25th reunion was the swim he and Dr. Emory had in Lake Tarleton in June, a month when its northern water is usually cold enough to chill nearly everyone's enthusiasm.

FOLLOWING the award of his doctorate in 1926, Dr. Small found himself with his wife on a steamer bound for Europe on a Sheldon Travelling Fellowship, awarded through the recommendation of Professor Conant. Under Dr. Wieland in Munich, Dr. Small desiring a new field of research chose morphine in particular and narcotics in general, and he has since devoted the major portion of his time, imagination, and efforts to them.

The Smalls loved the Germany of the days before Hitler. One week end with Donald Bartlett '24, now Professor of Biography at Dartmouth, they climbed the Benediktenwand, a mountain near Munich about as difficult as Chocorua. The Smalls climbed all over the Bavarian Alps. They climbed through the Tyrols into Switzerland. And with Bill Pepin '18, a Lowell dentist, Red climbed the Matterhorn over the classical tourist route. It cost him 14 hours of intense exertion to get to the top where because of a blizzard he could not see a thing. The Smalls climbed Mt. Etna in Italy, "the most beautiful in the world." Equally enchanting were Faltboot trips with groups of Germans down the Rhine and part of the Danube. One Easter vacation was spent in Graz where Dr. Small worked on microanalysis. He was one of the first to introduce it into this country.

After Dr. Small's return to the United States he went to the University of Virginia where he organized the chemical research for the Committee on Drug Addiction of the National Research Council, which was operating under the Rockefeller Foundation. He brought over some of the best minds from Vienna when he set up his laboratory and from modest beginnings he built up his staff until he had 15 or 20 workers.

At the same time a clinical laboratory in Michigan under the leadership of Dr. Nathan B. Eddy carried out the pharmacological work. "That period from 1928 through 1939 was the most prolific of my career," Dr. Small recalls. "I had ideal conditions for the stimulation of ideas and for successful research. I had to teach only one course, Microanalysis, which I had studied under Professor Pregl. The rest of the time I spent working with graduate students producing new drugs and observing their physiological effects."

In Charlottesville during this productive period Dr. Small's mother died of cancer in his house. He had an excellent opportunity to observe at close quarters how morphine was far from being the perfect palliative. She provided an additional incentive to find a better drug. More than ever he wanted to be able to do something to relieve agony in human beings condemned to the slow torture of incurable cancer.

Since 1937 Dr. Small has been Editor-in-Chief of the Journal of Organic Chemistry. He says stoically, "It takes a lot of time, but someone must do it." He feels strongly about the importance of scientific articles in journals and prefers to publish them rather than to write books. Many of his colleagues keep urging him to collect odds and ends, shape them up, get them between the boards of a book, as if that carried more prestige.

"I'm in no hurry to publish books," says Dr. Small, who has a long list of learned articles to his credit. "Look what happens to a book. After a few years it is dead. It gets lost. Who cares about a scientific book of 1830? Perhaps you cannot even find it. But a man's research written in the scientific journals remains. Step by step later, scientists go over his work. Once anyone begins to work on a subject, he must go back to the scientific journals to see what has been done."

He remembers still how impressed he was in his younger days when he kept running across names of men in the 19th century who had made important contributions to science.

"Yes," he says earnestly. "That permanence and survival is the true immortality. That is why I have edited the Journal of Organic Chemistry all these years. Long after I am dead and forgotten, 200 years from now, I will remain alive in the scientific publications, and people can find me. That is, if there any people left alive in 200 years."

No cynic by nature though he poses as one, Dr. Small is pessimistic about the probability of war, the ignorance of persons concerning its nature, and the chances of the earth as we know it today to survive. He thinks that despite awful destruction we might come out on top if a war were fought within the next five years but after that we cannot expect victory, for our present secret weapons will then be known to others. He regrets, however, loose talk about a preventive war.

"With another war," says Dr. Small gravely, "this earth will become like Mars. In World War II Europe had nothing except a few minor bombs, yet even so children are running around in rags and buildings lie in ruins and rubble. Einstein is right: there simply must not be another war. It would mean destruction people cannot comprehend for long that the world will be so ravaged that there will be no human life capable of surviving on it. I am very pessimistic. The physicists know what is involved."

Dr. Small knows from his personal experience anxieties parents go through in war though he did not experience ultimate tragedy. His son Donald was in submarine warfare for many months in the South Pacific, and once his sub got a six-inch shell in its conning tower, which forced it to limp back on the surface to port in a highly vulnerable condition. But Donald came through safely. Now, aged 25 and married, he is at Stevens Tech in Hoboken studying to become an engineer.

Now that Dr. Small is going on 52, he is easing off on mountain climbing and he works out instead on a woodpile on one side of his brick house. He burns extra wood with extra pleasure. "When I say no more mountain climbing," he hastens to add, "I mean that Moosilauke is O.K. But real mountain climbing is out. You know, the Matterhorn for 14 hours with 50 pounds on your back, a temperature of 20 degrees below zero, and a blizzard."

When he has time to go from his laboratory beyond his woodpile, he heads towards a cottage he owns in North Carolina where he cannot be reached by telephone. He was pleased that Dr. Ned Shnayerson, the New York surgeon and John Carden, the Boston advertising man, both '20, looked him up there. He enjoys fishing in the surf for channel bass, "stripers," as they are called, officially rock bass, which run up to 45 and 50 pounds. But a greater delight is for him to swim out to a tanker wrecked and split in two off the coast. There he puts on goggles, dives down into 25 feet of ocean and spears sheepshead weighing up to 15 pounds and tautogs up to 12. A good kill is 15 a day. As he needs not more than a couple of pounds of fried fish a day for himself and his wife, he walks up and down the beach distributing a couple of hundred pounds. During the winter months that he is at home, he makes fish spears by hand in his little workshop off his basement rpom.

Dr. Small loves the trees on his estate and his songbirds and is an enemy of their enemies. In faded and worn dungarees and in bare feet he was found on one July morning with a pair of bird glasses peering up high into his trees to see whether a cuckoo was a blackbill or a yellowbill.

"We don't often hear one around these parts," he said. "You know, it does not sing 'cuckoo' like the English variety that goes in for repetitious calling in the style of a whipporwill. Our American cuckoo barks like a squirrel. If I cannot make up my mind clearly as to whether it is a blackbill or a yellowbill, I shall be unhappy all summer."

At any season he may be seen toting a gun about his four acres of woods and fields, but such hunting expeditions which yield nothing more than a few squirrels and chipmunks are more symbolic than real. Not that he does not like real hunting; he does. He can tell stories of how he goes out with negroes and dogs for possum in Virginia. He is still less expert than the negroes who in the pitch dark can tell by the timbre of the dogs' barks whether a possum is climbing up a tree, skulking through the brush or crawling along a fence.

But Dr. Small hunts only occasionally for the exercise rather than for sport or food. "I have never eaten possum," he says. "They may be good eating; I should think they would be; but I give them away to the negroes. They consider them a delicacy, but possums look too much like rats for me to enjoy carving them up on a platter and putting them hot into my mouth."

Dr. Small's researches and the number of articles he has to examine for his scientific magazine use up most of his eyesight, and evenings he shies away from recreational reading. He subscribes to TheNew Yorker, the Saturday Review of Literature, and the National GeographicMagazine, but he is usually six months behind on them.

All of Dr. Small's friends consider him a man of violent actions and language. He is rarely lukewarm about anything; he is almost always violently pro or anti; and he speaks his mind in no uncertain terms. His main loves are his wife and home in Bethesda and his cottage in North Carolina, water that can be swum and fished in, mountains, and chemistry. His main hates are cats and hotheaded scientists who rush into print with lurid statements about scientific discoveries. He considers that even a doctor with an M.D. who by jumping to optimistic conclusions arouses illusory hopes in the afflicted is downright immoral, though he would not use words with such an ethical flavor. Inaccurate and smug assertions that diseases are "licked," as one popularizer did in the early days of malaria research, infuriate him. He can say violent things even about a President of the United States if a President puts too much heat on him to produce a new drug, even in time of war or just before it and even if thousands of lives are to be saved.

Comparing the work which he has done with the work which he had planned to do, he is severe about himself. Nor does he consider that he has won many honors. The one he is perhaps proudest of is his election to the National Academy of Science, founded by Abraham Lincoln, which is the American equivalent of the Royal Society founded in London in 1645. Members meet twice a year. Their function is to give advice in emergencies but only on request. During the war the Government challenged them with a number of definite problems.

One of Dr. Small's great satisfactions in Government work is that he is left alone. If a fortnight goes by without some sort of result, no one comes around pestering him. The only question ever asked is whether the research is sound. The public are understanding too. The contributions made to science by Becquerel, the discoverer of radio activity, and by Madame Curie have made them conscious that what is important is not what a scientist turns out for a deadline and a headline. Rather it is what after controlled and responsible testing he turns out for ultimate human good.

LABORATORY DAYS IN MUNICH: Dr. Small, in Bavarian costume, with some of his colleagues in Dr. Wieland's laboratory, where he first started to specialize in narcotics and in the study of morphine.

AS AN UNDERGRADUATE, the future chemist of international repute was an ardent Outing Clubber, spending practically all of his free time on cabin trips, mountain climbing and skiing in winter.

FALT-BOATING ON THE DANUBE with Mrs. Small is one of the pleasant memories Dr. Small has of the period as Sheldon Fellow in Munich. Above they are shown traveling from Innsbruck to Vienna.

AT HIS NORTH CAROLINA RETREAT, a few years back, "Red" Small displays two of the big channel bass for which he still likes to cast in the surf.

THE SMALL FAMILY, shown in this recent photograph, includes daughter Ruth, standing with Mr. and Mrs. Small; and son Donald (right) holding baby David. Donald's wife Rosemary is next to him with Lyndon F. II, and Ruth's husband, Ned Farren, is at the left with Teddy (Edward Lyndon).