Going Beyond the Accidental Discovery

1. Going Beyond the Accidental Discovery What the Great Researchers Did Next Rajesh Shah March 2004

2. Chance or Destiny • “…chance favors only the prepared mind” – Louis Pasteur • Great discoveries are often made not because they are sought, but because they are chanced upon • Rosetta Stone (Napolean’s army) • Americas (Columbus) • Aspartame (Jim Schlatter) • But what distinguishes great discoverers are their own characteristics and the next steps they take • …and so it is with medicine

3. A Quick Case • A 49 year old alcoholic man presents to the emergency room with severe dyspnea • It began 10 days prior and has been followed by chills, fever, night sweats, cough productive of currant-jelly sputum and a temperature to 40° C • A few hundred years ago, knowing the cause, obtaining a diagnosis, and effectively treating this would have been difficult

4. From Humble Beginnings… • Antoni Van Leeuwenhoek (1632-1723) • Schooling – Apprentice in a dry-goods store in Amsterdam • Work – Janitor at Delft, Amsterdam town hall

5. An Obsession with Perfection • Leeuwenhoek was the quintessential perfectionist • Learned lens grinding from spectacle-makers, and metal extraction and fashioning from goldsmiths • Made his own microscopes and his own settings

6. A Suspicious Eye • Leeuwenhoek did not trust anyone, often times not even himself! • Would not buy microscopes, but build them (hundreds of them) instead • Would hesitate to let anyone even touch his microscopes, and would never sell them • He would never teach others any of his skills, particularly how to build microscopes

7. An Insatiable Curiosity • Leeuwenhoek began looking at everything he could see under his microscopes • He looked at animal parts, bugs, and bee stingers • He was the first to confirm William Harvey’s theory of circulation by visualizing capillaries • And then he decided to look at something no one else had ever thought of…

8. And a Stroke of Luck • One day, he decided to take a look at clear water that had collected after rainfall in a bowl • What he saw shocked him – little “wretched beasties” (bacteria, as we would call them today)

9. A Belief in Disbelief • Leeuwenhoek did not believe what he saw, and would look over and over through his microscope • He devised simple experiments to make sure the bacteria did not come from other sources • Even then, he did not tell anyone of his discoveries, but looked at water from other places

10. An Important Collaboration • Leeuwenhoek, after tedious and careful observation, finally conveyed his observations to the Royal Society of England, one of Europe’s foremost scientific societies • He had been in communication with them for years, but this time sent affidavits from prominent Delft townsfolk • Soon after, he was made a Fellow of the Royal Society

11. A Keen Eye for Observation • Leeuwenhoek lived in a time when the scientific approach was changing – observation and questioning was becoming more important than theorizing and accepting • Leeuwenhoek, then, was the model scientist in that he communicated only what he observed (along with some details about his everyday life)

12. …To a Distinguished End • In his lifetime, Leeuwenhoek was visited by Peter the Great of Russia, the Queen of England, and was famous throughout Europe • He is considered by many the first microbiologist

13. Why Did Leeuwenhoek Succeed? • Dedication to perfection • Common sense • Constant checking and re-checking of observations • Communicated his findings • He was lucky!

14. From the Birth of Microbes to their Death – Alexander Fleming • Alexander Fleming 1881- 1955 • Attended University of London, then Saint Mary’s Hospital for medical school • Made his fortune by treating syphilitic patients • Also had a large art collection obtained by treating syphilitic artists

15. Fleming’s Research – Antiseptics • Fleming did not believe in Lister’s theory of antiseptic use for wound infections • Fleming wanted to prove that chemical antiseptics were ineffective in treating infections and that it was better to use the body’s own immune system • He also had a pessimistic mindset against chemical antimicrobials, which he viewed as toxic (common in those days) • He thus experimented with lysozyme, a natural product of the body, to treat infections

16. One Fateful Day…. • One day in 1928, Fleming opened up a petri dish to smear it with a strain of Staphylococcus • That simple action changed medicine, and microbiology, forever

17. The Discovery (or Re-Discovery) of Penicillin – Circumstances in 1928 • Penicillium notatum molds were growing one floor below Fleming’s laboratory • Fleming inoculated petri dishes with Staphylococcus for lysozyme experiments • He did not place the dish in an incubator (which would have prevented Penicillin growth) • A heat wave broke the day he left for vacation, allowing the Penicillium notatum to grow

18. Penicillium’s Strange Effect • Fleming discovered the area around the Penicillium had no Staph growth • Fleming had made a similar discovery when he sneezed on a petri dish and discovered bacteria did not grow around his secretions b/c of lysozyme in the mucous 6 years earlier

19. The Re-emergence of Penicillin • Fleming was not the first to discover Penicillin, John Tyndall had discovered it in 1875 • Was not known at that time that bacteria caused illness • Tyndall did not explore the antibacterial phenomenon closer

20. A Determined Investigation • Fleming, unlike Tyndall, decided to investigate the phenomenon • He made a canal filled with Penicillium broth in an agar plate and streaked different bacteria across the canal to see which bacteria were affected

21. Still More Experiments • Investigated other species of Penicillium • Injected some into a live rabbit and found no toxic effects • Treated an infected eye, an inflamed maxillary sinus, and an amputated leg, of which the first two healed completely • Interestingly, he never experimented with syphilis

22. A Puzzling Stop • Fleming then stopped his research because, as he later recounted, his preparations quickly lost their anti-bacterial effects • He also wanted to continue his research in lysozymes, which he had been working on for years • He did write a paper, however, in 1929 which saved his findings from obscurity

23. The Arrival of Florey and Chain • Dreyer, Campbell-Renton, and Ernst Chain • Florey and Chain experimented with penicillin, purified it, administered it without side effects, and realized it could treat infections anywhere in the body • Published results in August of 1940 • Fleming, Chain, Florey awarded Nobel Prize in 1945

24. Howard Florey and Ernst Chain

25. Why did Fleming Succeed? • Fleming had an eye for noticing seemingly inconsequential things • Fleming was already working on antibacterials, and so was very observant of antibacterial phenomena • Fleming was too good of a scientist to let his observations go unexplored, and results to go unpublished • He was lucky!

26. Wilhelm Roentgen and a New Kind of Ray • Wilhelm Conrad Roentgen 1845-1923, born in Germany • As a young boy, was asked to reveal the identity of a classmate who had drawn a caricature of a teacher in school • He refused, and was expelled

27. The Consequences • His expulsion meant he could not receive his diploma certifying he graduated • Without his diploma, he could not enroll in a University and thus could not become a surgeon or lawyer

28. Obstacles • Roentgen found he could enroll at the Polytechnical School in Zurich simply by passing their entrance exam • Roentgen obtained a degree in mechanical engineering and became the protégé of Dr. August Kundt, one of the most famous theoretical physicists of the time

29. Determination Unbound • Through the help of Kundt, Roentgen was finally able to overcome his educational barriers and attain a full professorship at the University of Giessen in 1876

30. Cathode Ray Tube and Crooke • Sir William Crooke in England was studying, at the end of the 19th century, the effect of electricity on rare gases, and so developed the Crooke’s tube (left) • Colored lights would appear at the cathode end of the tube when electricity was applied, and so cathode rays became a subject of great interest during this time

31. Lenard’s Experiments • Phillip Lenard used a modified Crookes tube with a covered window with which he proved that cathode rays could escape the tube and cause a barium platinocyanide crystal to fluoresce • Roentgen wanted to repeat these experiments, and so Lenard sent him a Crookes tube with a covered window

32. Roentgen’s Confusion • On Nov 8 1895, with the Crookes tube, Roentgen tried to take Lenard’s experiment a step further to see if cathode rays could pass through glass • It was then that he noticed an eerie, green glow a yard away from him in his pitch black basement workroom

33. A Realization • Roentgen, thinking he was imagining, repeated the experiment over and over • He realized the glow was coming from a barium platinocyanide screen some distance from his bench • He also realized it could not be due to cathode rays because they traveled only short distances • It must be a new ray – an “X” ray

34. More Experiments (and Luck) • Roentgen wanted to see what these new rays could pass through • He used many different objects including wood and metal weights • At one point, he held a lead pipe up and noticed something…he could see the bones in his hand

35. Not the First • But Roentgen was not the first to notice these phenomena • Crookes had noticed photographic plates in his lab were stained with shadows (he sent a letter of complaint to the manufacturer) • Lenard, too, observed the same phenomenon as Roentgen but never decided to investigate

36. Secret Proceedings • Roentgen immediately realized the importance of his discovery • He would barely eat, sleep, or talk with his family for the next few weeks • He told no one about what he had seen, except his wife

37. Dedication for Publication • He rushed together a preliminary report within 7 weeks, and was able to get it published in the proceedings of the Physical-Medical Society of Wurzberg annual meeting • He knew it would not be widely read, so he also sent copies on January 1 1896, with the x-ray of his wife’s hand, to six of the most prominent physicists in Europe

38. Some Public Promotion • A newspaper in Vienna picked up the story, and published the details on January 5 • On January 6th, the London Chronicle printed the story • Roentgen instantly became famous worldwide

39. A New Prize • Roentgen received the first Nobel Prize in 1901 in the field of Physics "in recognition of the extraordinary services he has rendered by the discovery of the remarkable rays subsequently named after him."

40. Why did Roentgen Succeed? • Did not let unusual observations go unstudied • Was very methodical and thorough in his experiments • Went through the extra effort (and extra cost) to ensure his results were noticed • And, of course, luck!

41. Back to Our Case • So what would we do today? • Get an x-ray (Roentgen) • Get a sputum examination to observe the bacteria (Leeuwenhoek) • Treat with antibiotics (Fleming) • So, in many ways, we are lucky that we can treat a pneumonia today!

42. In Conclusion – Some Common Traits • Passion for what they did • Keen eyes for observation • A willingness to publish • A strong determination • But uncommonly, they had different personalities • Leeuwenhoek was arrogant • Fleming was shy • Roentgen was a hard, honest worker