Clicker Question

1. Clicker Question Which of the following process(es) that occur(s) at a synapse could be targeted by a drug designed to treat mental illness? A) Secretion of the neurotransmitter B) Binding of the neurotransmitter to a receptor C) Degradation of the neurotransmitter D) Re-uptake of the neurotransmitter E) All of the above and more

2. Where are we? • Last time I discussed… • that before the introduction of psychopharmacology, mentally ill patients were treated barbarically. • the brain is a trillion cauldrons of chemical activity in which neurotransmitters in the synapses regulate the transmission of electrical signals. • how psychopharmacological drugs influence the concentration of neurotransmitters in the synapses. • that while we understand a lot about the physico-chemical processes that take place in the brain, we still do not understand the mechanism of normal and abnormal thinking and the way the psychopharmacological drugs work. • This time I will discuss… • immunity—how the body protects itself from invaders. • the innate immune system. • the acquired immune system that, like the nervous system, can learn, remember and recognize self from non-self. • allergies, anaphylactic shock and autoimmune diseases.

3. The human body is capable of resisting many harmful disease-causing agents in the course of everyday life. • Not everyone in a family, dorm, sorority, fraternity or classroom is equally resistant to disease. • Luckily, immunity (from the Latin word immunis meaning “free of”) against disease can be conferred to sensitive people though vaccinations.

4. The Ancients Realized that Survivors of a Disease were often Immune to Getting that Disease Again • In 429 BC, Thucydides noticed that smallpox survivors did not get re-infected. • In the 10th century, also realizing that survivors of small pox were immune to the disease, Chinese doctors put the fluid from small pox pocks into the noses of susceptible people to protect them from small pox.

5. Puritans Learned that Africans also Inoculated People to Make them Immune to Small Pox • In 1706, the Puritan minister, Reverend CottonMather, learned from a slave named Onesimus, that he had been inoculated with small pox as a child in Africa as a protective measure. • Courageously going against the Church and State, in 1721, during the small pox epidemic in Boston, Cotton Mather and Dr. Zabdiel Boylston inoculated the people. ,

6. Lady Mary Wortley Montagu (1721), the wife of the British Ambassador to Turkey, brought back to England a method of preventing the deadly small pox disease. • Physicians would take a small amount of pus from the pocks of a person with a mild case of small pox and rub it in to a scratch in the arm of a healthy person. • Unfortunately, the healthy patient often contracted a full blown case of small pox and died.

7. Edward Jenner Jenner (1798) and many milkmaids he treated noticed that people who got cow pox (variolae vaccinia) were immune to the deadly small pox. One day, when Sarah Nelmes came to him with cow pox, he decided to see if inoculating someone with cow pox would prevent them from getting small pox. He took pus from Sarah Nelmes’ pocks and rubbed it into scratches in James Phipps’ arm. The 8 year old son of the gardener developed cow pox. Once he was over the cow pox, Jenner exposed him repeatedly to small pox, but he had become immuneto the small pox virus.

9. A Profile in Courage: Edward Jenner • Jenner reported his results to the Royal Society; however, Sir Joseph Banks, the president of the Royal Society suggested that he should not risk his reputation by presenting something "so at variance with established knowledge". • Thankfully Jenner used his meager savings to publish his work privately and within a few years vaccinations for small pox became common practice.

11. Cholera: A Bacterial Infection • Cholera is transmitted from person to person by the fecal-oral route resulting from drinking water contaminated with feces that contain the bacterium, Vibriocholerae. • Vibriosecretes a toxin into the intestine that results in massive diarrhea followed by dehydration. • If the patient is not rehydrated orally or and/or intravenously within hours of being infected, death can result. • Cholera can also be prevented by a vaccine.

12. Louis Pasteur Had a Prepared Mind • Louis Pasteur (1880) reasoned that if a vaccine could be found for small pox, then a vaccine could be found for all diseases. Pasteur found a vaccine against chicken cholera by chance. • One of his colleagues had inoculated chickens with chicken cholera bacilli from an old culture and the chickens did not get sick. Even when he exposed these chickens to fresh chicken cholera bacilli that would kill other chickens, the chickens who were exposed to the old strain first still did not get sick.

13. Louis Pasteur Had a Prepared Mind • Pasteur reasoned that the potency to cause cholera in chickens had attenuated in the old culture. • He guessed that the chickens used the weaker germs to form a defense against the more powerful germs in the fresher culture. • Pasteur pioneered the use of attenuated bacilli for vaccinations, a word he coined in honor of Jenner.

14. Anthrax • Anthrax is often a fatal disease characterized by hemorrhaging and tissue decay. • It is caused by a toxin produced by Bacillus anthracis, which can enter the body through the lungs, skin or intestines.

15. Louis Pasteur and Anthrax Pasteur (1881) aged cultures of anthrax to weaken them and used the weakened germs to make a vaccine. The idea that germs could make an animal healthier seemed unbelievable and Rossignol, the editor of The Veterinary Press, challenged Pasteur to a public test. Pasteur inoculated twenty five sheep with his vaccine while twenty-five were not. Subsequently, all fifty were injected with anthrax. Those injected with the vaccine lived while those that were not inoculated died within two days.

16. Rabies • Rabies is a fatal disease characterized by the inflammation of the brain. • Rabies is caused by the rabies virus, which is found in the saliva of an infected animal. • Rabies is often transmitted by a bite.

17. Louis Pasteur, Joseph Meister, Human Experimentation and Rabies • Pasteur injected healthy dogs with aged rabies germs (viruses) from the spinal cord of rabid rabbits. The vaccinated dogs became immune to rabies. • A 9 year old boy named Joseph Meister was bit by a rabid dog. Since the boy would have died had he been left untreated, Pasteur (1885) reluctantly took the risk on treating Joseph Meister with the vaccine that had only been tested on dogs. • Happily, the vaccine worked and the boy survived to become the caretaker of the Pasteur Institute.

18. Pasteur’s Father and Mother Painted by Louis Pasteur, Himself

19. The Wisdom of the Body in the Fight Against Infectious Diseases The body protects itself from infectious microbes in two ways: • Innate Immunity (skin, phagocytes, interferon) • Acquired Immunity (B and T lymphocytes)

20. The Body’s First Line of Defense: Innate Immunity • Skinand the mucosa lining the digestive and urogenital tracts are physical barriers to disease, although a tiny cut will allow pathogens to enter the body. • Sweat, saliva and tears contain lysozyme, an enzyme that degrades the cell wall of gram positive bacteria. This causes the bacteria to lyse. Lysozyme was discovered by Alexander Fleming in 1922. • The respiratory tract is guarded by the hairsin the nostrils as well as the mucus that traps microbes and cilia that sweep the mucus out of the respiratory system and down the esophagus. • The hydrochloric acidproduced by the parietal cellsin the stomach kills microbes (with the exception of Helicobacter) that come from the respiratory system or enter the body along with food.

21. The Inflammatory Response: Phagocytes and Pus • Microbes that breach the first line of defense are accosted by the white blood cells which are found in the blood, the interstitial fluid, and the lymph. • The white blood cells that engulf microbes by phagocytosis are known as phagocytes. The neutrophils, which are a kind of phagocyte that most rapidly fights infections, make up most of the pus that occurs with an infection. nobelprize.org/educational_games

22. Ilya Mechnikov In 1882, Ilya Mechnikov was studying the larvae of starfish. He noticed that when he inserted a splinter into the larva, strange cells gathered at the point of insertion. The cells surrounded the splinter, eating any foreign substances that entered through the ruptured skin. Mechnikov named these new cells phagocytes from the Greek words “eating cells.”

23. Splinters “Sharp splinters were introduced into the bodies of these Bipinnaria and the next day I could see a mass of moving cells surrounding the foreign bodies to form a thick cushion layer. The analogy between this phenomenon and what happens when a man has a splinter that causes inflammation and suppuration is extraordinary.”

24. Disease: A Fight Between Microbes and Phagocytes • This observation led Mechnikov to propose that in humans, phagocytes move to the wound and engulf the bacteria. • “…disease would be a fight between the morbid agent, the microbe from outside, and the mobile cells of the organism itself. Cure would come from the victory of the cells and immunity would be the sign of their acting sufficiently to prevent the microbial onslaught.”

25. Ilya Mechnikov “Photographs taken of him when he was working at the Pasteur Institute show him with long hair and an unkempt beard. It is said of him that at this time he usually wore overshoes in all weathers and carried an umbrella, his pockets being overfull with scientific papers, and that he always wore the same hat, and often, when he was excited, sat on it.”

26. The Inflammatory Response

27. The Inflammatory Response • When the skin is broken, damaged mast cells release histamine (which causes one to burn and itch). The histamine diffuses to the capillaries and cause them to dilate and become leaky. • The phagocytes and components of blood plasma move out of the leaky capillaries. This results in redness and swelling. The swelling puts pressure on the pain receptors. Consequently, the inflammation leads to pain. • In the interstitial fluid, the phagocytes known as neutrophils rapidly engulf microbes and dead or injured body cells. • The pus at the site of injury consists mostly of interstitial fluid and dead neutrophils.

28. Stinging Nettle Causes Inflammation Because It Contains Histamine • The hairs of stinging nettle contain histamine, acetylcholine and serotonin. • These molecules that occur in the plant and animal kingdoms cause itching, burning, reddening and swelling when you touch the hairs of the plant, informing you that the plant you touched is Urticadioica.

29. Phagocytes, Antioxidants and Free Radicals • The phagocytes kill the invading bacteria by producing a dose of free radicals (including superoxide), which are produced by the phagocyte itself. • Vitamin C is necessary as an antioxidant to protect the phagocyte from its own high dose of superoxide.

30. Corticosteroids and Anti-Inflammation • Cortisolreleased during stress suppresses the inflammation response. In the short term, this minimizes the pain associated with inflammation; but in the long term, it makes it easier to succumb to germs. • Synthetic corticosteroids (hydrocortisone) are used topically to treat the pain and itchiness of dermatitis, eczema, psoriasis, hemorrhoids, and poison ivy or nasally to treat allergy symptoms.

31. Zits • Acne occurs during puberty when androgens produced by the adrenal glands in men and women stimulate secretion of oils from the sebaceous (oil) glands beneath the skin. • The oil glands, which are exocrine glands, continuously secrete oil in order to lubricate the skin. • Cells that are close to the opening of an oil gland block the duct and cause a buildup of oil beneath the skin. Bacteria feast on this oil and trigger the inflammation response. • If the inflammation is near the surface, you get a pimple and if it is deeper, you get a boil. • When the oil breaks though to the surface, you get a whitehead and the oil becomes oxidized, it turns black and you get a blackhead.

32. Causes and Preventative Measures • The three basic causes of acne • Oil from sebaceous glands • Clogged pores • Bacteria • Three preventative measures • Minimize oil (wipe away with mild astringent; or kill oil producing cells with laser). • Unclog pores (soap and water; alpha-hydroxy acids or beta-hydroxy acids) • Kill bacteria (benzoyl peroxide)

33. Alpha-Hydroxy Acids Lactic acid (from milk) Glycolic acid (from sugar beet and sugar cane)

34. Beta-Hydroxy Acids • Salicylic acid, isolated from the bark of willow (Salix) trees and Spiraea bushes, is involved in the “systemic immune response” of plants. • Notice the greater proportion of CH bonds in this beta-hydroxy acid than in the alpha-hydroxy acids. • This makes salicylic acid more soluble in oil (more nonpolar) so it penetrates more deeply into the oil ducts.

35. Innate Immunity Against Viruses: Interferons • Interferons are proteins that are produced by virus-infected cells that help other cells become resistant to viruses. • The interferon gene from the infected cell is transcribed and translated to make interferon, which is secreted from the cell and diffuses to the neighboring healthy cells. • The interferon stimulates the healthy cells to make antiviral proteins.

37. Recombinant DNA Technology Makes Interferon Cheap and Accessible for the Treatment of Hepatitis and other Viral Infections

38. The Immune System:The Mind Body Connection IL-6 is produced by the white blood cells that participate in the innate immune response. Participants looked at a 10 minute slide show of people holding guns or people with disease symptoms. After seeing pictures of the sick people, the interleukin-6 (IL-6) level in the participant’s blood rose significantly. The increased levels of IL-6 can give a boost to the entire immune system. Psychology Today Psych Sci

39. Our Blood—Our Identity • Experience with blood transfusions indicate that our body can distinguish between our own blood and the blood of others. • Karl Landsteiner found that the red blood cells in the blood seemed to fall into four groups (A, B, AB and O). • Jean Dausset, Baruj Benacerraf and George Snell found that the white blood cells (as well as all the other cells in our body) also have proteins, now known as the major histocompatibility complex, in their plasma membranes that represent our self.

40. Karl Landsteiner (1930):Our Blood and Our Biological Individuality • Anthropological Studies • Northern Europeans are mostly Type A. • Asians are mostly Type B. • American Indians are mostly Type O. • Forensic Studies • Tests of blood found at a crime scene has been used to acquit innocent people. • Paternity Tests • Blood tests has been used to exclude a putative father.

41. Karl Landsteiner

42. Jean Dausset, Baruj Benacerraf and George Snell

43. John Galbraith Simmons: The Self “The self is not just a narrative fiction of language and mind, nor is a physical structure its only boundaries. The self may also be said to exist on a molecular level, comprised of a group of antigenic proteins found in all cells of the body. The specific complexion of these antigens is configured by a set of genes known as the “major histocompatibility complex” (MHC).”

44. Peter Medawar and Macfarlane Burnet: Acquired Immunity (1960) • If the innate defenses can not eliminate an infection, the immune system kicks in. • The immune system provides acquired immunity, consisting of humoral immunity and cell-mediated immunity. • Whereas the innate system may be effective before one is exposed to a microbe, the immuneresponse develops after exposure to microbes. • The immune system is triggered by an antigen, a molecule that is foreign to the host’s body.

45. Peter Medawar (1946):The Uniqueness of the Individual “Philosophy and common sense, though often parted, have long agreed about the uniqueness of individual man. Different men have different faces, sizes, shapes and origins; different aptitudes, skills and predilections; and different ambitions, hopes and fears. Science now makes it a trio of concordant voices, for the uniqueness of individual mice and men is a proposition which science can demonstrate with equal force, perhaps with deeper cogency, and certainly with a hundred times as much precision.”

46. Books by Peter Medawar

47. Books by MacFarlane Burnet

48. Clonal Selection Theory How does the immune system recognize so many different foreign particles, mobilize against them and remember them? MacFarlane Burnet suggested that it “would make real sense if cells produced a characteristic pattern of globulin [antibody molecule] for genetic reasons and were stimulated to proliferate by contact with the corresponding antigenic determinant.”

49. Antigens Generate the Proliferation of Antibodies • Proteins that make up the coats of viruses, the surfaces of protozoa and other parasites act as antigens. • Carbohydrates from the walls of bacteria and fungi also act as antigens. • Various venom and toxins that get into the blood stream also act as antigens. • Vaccines act as antigens. • Unfortunately, proteins from the surface of donated blood cells, tissues and organs also act as antigens.

50. Antigen: Antibody-Generating Substance • An antigen triggers the immune system to produce large quantities of the antibody that will bind to it. • An antibody is a protein found in the circulatory system that specifically binds to an antigen with high affinity. • The immune system, like the brain, learnsabout the antigens to which a host is exposed and has a memory which allows it to react rapidly against an antigen it has experienced before.