Science Makes Our World

1. Science Makes Our World Livable and Humane

2. Mathematics Makes Our Science Efficient In the few cases where we can use it!

3. Medicine is one of the Oldest Professions

4. Medicine was an ArtforThousands of Years

5. As we makeMedicine into a Science, Practical Benefitsto everyday life will be Immense!

6. Medicine was an ArtforThousands of Years

7. But until Antibiotics Almost Nothing Worked

8. Surgery was severely limiteduntil anestheticsSurgery was severely limited until IV drips allowed control of Acid-base and Fluid Volume

9. Anesthetics, IV drips: discovered by Physician-ScientistsAcid-Base, Fluid-Balance: developed by Scientists, using mathematics.IV drips were made routine by Surgical Nursesas much as Physicians

10. Medicine was an ArtforThousands of Years

11. But until Antibiotics Almost Nothing Worked

12. Doctors watched Pneumonia Victims, Live or Die.Parents would not let children roam because blood poisoning killed so many!Every sore throat was a Nightmare !

13. Typhoid Fever,diarrhea, cholera killed millionswith children dying in arms of their parents after lingering deaths of weeks

14. No one recovers from the death of a child…..in their arms!

15. Do you know the treatment today for food poisoning, diarrhea, and even typhoid fever and cholera?

16. The treatment is (almost) nothing.It is (almost) my grandmother’s Chicken Soup.The treatment is tomaintain hydration(i.e., the salts Sodium, Potassiumand water)

17. The treatment is tomaintain hydration(i.e., water and salts Sodium, Potassium)using the right liquidsPedialyteorGatorade!

18. Science Made Our World Livable and Humane By designing the right fluid!

19. Physics, Chemistry and Mathematics designed the right solution Not physicians!

20. What has made the difference?Medicine is Becoming a Science?

21. Science works byGuess and Check

22. Scientists make intelligent guesses (some of the time) but they Alwaysmake Honest Checks!

23. Science Makes Our World When the scientific method works, it WorksSpectacularly We calculate buildings(we do not make models) We calculate Airplanes(we do not make models)

24. Science Makes Our World When the scientific method works, it WorksSpectacularly We design new molecules for our most serious needs Cosmetics and Clothing

25. Science Makes Our World When the scientific method works, it WorksSpectacularly We create Digital Machines (chips) which double in speed every 1.5 years For 50 years, 250/1.5 10,8,226,394,0970 1.08×1010  

26. When the scientific method works, it works spectacularly We create Transistors which make Digital Machines (chips) possible, even trivial because Transistors follow Simple Equations Exactly (almost)

27. Science Makes Our World Imagine what will happen when we can deal with the Molecules of Lifeas well as we deal with the design of buildings and bridges, or cosmetics and fabrics!

28. But we cannot design a drug!

29. Science Makes Our World I am trying to understand an important class of molecules Ion Channels justas a Physicist or Chemist understands Cosmetics, Fabrics, or Digital Chips

30. OmpF Biochemist’s View Structure All Atoms View Chemical Bonds are lines Surface is Electrical Potential Red is positive Blue is negative Bob Eisenberg: beisenbe@rush.edu

31. Structure Na+ Bob Eisenberg: beisenbe@rush.edu Na+

32. Structure Na+ Na+ Bob Eisenberg: beisenbe@rush.edu

33. Note: intra-cellular compartmentsare defined by their membranes The Cell Defined by a Membrane Bob Eisenberg: beisenbe@rush.edu

34. Closed Channel Open Channel ION CHANNELS – Biological Role • Ion channels are Proteins that form nanoscale tunnels through the membranes of (nearly) all cells and subcellular sacks. • Ion channels regulate the transport of ions in and out of the cell. • Ion channels maintain intracellular ion concentration and electrical potential essential for cell life and function. • Ion channels control electrical signaling in the nervous system, contraction of heart and muscle, and many other functions. • Ion channels cause many diseases. Viruses attach to channels to enter cells • Ion channels are the targets of many drugs used in clinical medicine.

35. Current in One Channel Molecule is a Random Telegraph Signal

36. Lipid Bilayer SetupRecordings from a Single Molecule

37. Studying Channels Channels are studied as single molecules in Patch clamp and Bilayer set-ups. Both set-ups control ion concentrationsin the baths and the voltage across the membrane.

38. Voltage Step Applied Here (+ 80 mV; 1M KCl) Opening of Porin Trimer

39. Single Channel Currents have little variance

40. Goal: Predict Function From Structure given Fundamental Physical Laws

41. Goal: Predict Function From Structure given Fundamental Physical Laws

42. But … What are the Fundamental Physical ‘Laws’?

43. Verbal Models Are Popular but Inadequate They are not ‘laws’ at all!

44. Verbal Models areVagueandDifficult to Test

45. Verbal Modelslead to Interminable Argument and Interminable Investigation

46. and thus to Interminable Funding

47. and so Verbal Models Are Popular

48. Goal: Predict Function From Structure given Fundamental Physical Laws

49. What are the Fundamental Physical ‘Laws’?

50. The Essence of Engineering is knowing What Variables to Ignore! WC Randels quoted in Warner IEEE Trans CT 48:2457 (2001)