Waverly Hills Tuberculosis Sanatorium. Louisville KT 1926

1. “Wars and elections are both too big and too small to matter in the long run.  The daily work—that goes on, it adds up.  It goes into the ground, into crops, into children’s bellies and their bright eyes.  Good things don’t get lost. Here's what I've decided: the very least you can do in your life is to figure out what you hope for. And the most you can do is live inside that hope. Not admire it from a distance but live right inside it, under its roof. What I want is so simple I almost can't say it: elementary kindness. Enough to eat, enough to go around. The possibility that kids might one day grow up to be neither the destroyers nor the destroyed. That's about it. Right now I'm living in that hope, running down its hallway and touching the walls on both sides. I can't tell you how good it feels” From Barbara Kingsolver, “Animal Dreams”

2. Despite Koch’s discovery, for 60 years the only treatment was isolation, “fresh air, and sunshine” www.umdnj.edu/librweb Waverly Hills Tuberculosis Sanatorium. Louisville KT 1926 Built in 1911, expanded in 1926, closed in 1961

3. So it was time for another Nobel laureate! Selman Waksman 1888-1973

4. He was working on bugs that live in dirt! Selman Waksman 1888-1973

5. He was working on bugs that live in dirt! A childhood immigrant from the Ukraine, through hard work He became a professor Of microbiology and biochemistry at Rutgers Selman Waksman 1888-1973

6. He was working on bugs that live in dirt! A childhood immigrant from the Ukraine, through hard work He became a professor Of microbiology and biochemistry at Rutgers He coined the term antibiotic and Discovered more than 20 Antibiotics, including two which Are widely used today. Neomycin--check your medicine cabinet Selman Waksman 1888-1973

7. He was working on bugs that live in dirt! Streptomycin Streptomyces griseus.

8. He was working on bugs that live in dirt! Streptomycin Streptomyces griseus. Isolated on October 19, 1943 by Albert Schatz, a graduate student in Waksman’s lab

9. He was working on bugs that live in dirt! the-scientist.com Streptomycin Isolated on October 19, 1943 by Albert Schatz, a graduate student in Waksman’s lab

10. Bugs fight bugs Streptomycin kills many bacteria, including Mycobacterium Tuberculosis!

11. Bugs fight bugs Streptomycin kills many bacteria, including Mycobacterium Tuberculosis! But how?

12. The central dogma-- anybody remember that?

13. The central dogma-- anybody remember that? DNA -> RNA -> Proteins

14. The central dogma-- anybody remember that? DNA -> RNA -> Proteins

15. And we call that step? DNA -> RNA -> Proteins

16. Translation! DNA -> RNA -> Proteins

17. Bacteria do it too, and like us they use RIBOSOMES www.palaeos.com

18. Let’s zoom in on the action Lovely picture from Harry Noller

19. The ribosome is an amazing machine That unlike most in the cell runs on RNA! Lovely picture from Harry Noller

20. The ribosome is an amazing machine That unlike most in the cell runs on RNA! 16S rRNA + proteins =30S or small subunit Lovely picture from Harry Noller

21. If we zoom in further…

22. Luckily, our ribosomes are slightly different and thus streptomycin affects them less 16S rRNA + proteins =30S subunit Lovely picture from Harry Noller

23. Streptomycin cannot be given orally, but must be administered by regular intramuscular injection. An adverse effect of this drug is ototoxicity, i.e. It can result in temporary hearing loss.

24. Streptomycin cannot be given orally, but must be administered by regular intramuscular injection. An adverse effect of this drug is ototoxicity, i.e. It can result in temporary hearing loss. Cool fact--this may be due to effect on Mitochondrial ribosomes!!!

25. OK. So streptomycin kills bugs in a flask in the lab. What about inside a patient?

26. First we have to make a lot of it. In steps George Merck of Merck and Co.

27. First we have to make a lot of it. In steps George Merck of Merck and Co. And we got the patent…

28. First we have to make a lot of it. In steps George Merck of Merck and Co. But we gave it back to Rutgers!

29. Now we need to try it on animals. Enter Dr. William H. Feldman and Dr. H. Corwin Hinshaw at the Mayo Clinic

30. Now we need to try it on animals. Enter Dr. William H. Feldman and Dr. H. Corwin Hinshaw at the Mayo Clinic In two months they reported to Waksman that four tubercular guinea pigs receiving streptomycin "look exceedingly well." We do, don’t we!

31. OK, but how about people? Next Feldman and Hinshaw invent clinical trials www.jameslindlibrary.org

32. OK, but how about people? Next Feldman and Hinshaw invent clinical trials

33. OK, but how about people? Next Feldman and Hinshaw invent clinical trials This is really important!!

34. OK, but how about people? In August 1945 Hinshaw reported that thirty-three patients had been treated "and [we] continue to be quite optimistic."

35. Initially streptomycin appeared to be a miracle cure Patients, including the first, “Patricia T”, Were returned to health from death’s door

36. Now the problem was scaling up (Remember 5 million people a year Were still dying of TB!) By 1948 8 companies were making streptomycin But their 80,000 pounds Would only treat 1000 patients

37. Initially streptomycin appeared to be a miracle cure BUT…..

38. A second, much worse Problem was now on the horizon By 1948 patients began to relapse! For example the author George Orwell

39. But a second, much worse problem was now on the horizon In an MRC clinical trial, patients improved rapidly But within five years the death rate was the Same as the untreated controls Professor Hill of the MRC

40. But a second, much worse problem was now on the horizon In an MRC clinical trial, patients improved rapidly But within five years the death rate was the Same as the untreated controls Uh, oh. Professor Hill of the MRC

41. What was going wrong??

42. What was going wrong?? Streptomycin resistant bacteria could be cultured from these patients!

43. What was going wrong?? Streptomycin resistant bacteria could be cultured from these patients! How could That happen?

44. What was going wrong?? Streptomycin resistant bacteria could be cultured from these patients! How could That happen?

45. Have you heard The one about Natural selection?

46. What was going wrong?? evolution.berkeley.edu

47. And how did this happen? evolution.berkeley.edu

48. And how did this happen? evolution.berkeley.edu

49. And how did this happen? evolution.berkeley.edu

50. And how did this happen? evolution.berkeley.edu