City College of San Francisco Microbiology 12

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Introduction

You will soon see that microbiology is a vast field with many subdisciplines. Microbiology 12 aims to give you a broad overview of the field but it is impossible to cover everything in depth. We will focus on the areas of microbiology that are important for your career as an allied health professional.

Some of the sub disciplines we will explore include:

Bacteriology	Study of prokaryotic microbes (bacteria)
Virology	Study of acellular, intracellular parasites (viruses)
Mycology	Study of fungi including yeasts, molds and mushrooms
Parasitology	Study of parasites. Typically this field has focussed on protozoa and helminths (worms)
Entomology	We will focus on insects and other arthropods that are of medical importance
Microbial metabolism	An understanding of the chemical pathways used by microbes with an emphasis on microbial identification
Microbial genetics	How microbes transmit, inherit and regulate genetic information
Microbial ecology	How microbes interact with each other and their environment
Microbial pathogenesis	How microbes produce disease
Immunology	An understanding of the body's defense system against infection and disease
Epidemiology	Become a 'disease detective' and understand the factors that contribute to disease origins and transmission.
Antimicrobial drugs	We will focus on the action of antibiotics and the growing problem of drug resistance
Genetic engineering	Manipulating microbes to make beneficial (we hope!) products

Early microbiology

Ancient cultures and civilizations had no idea that microbes existed but they did comprehend some of their important effects. For example:

• Ancient Egyptians were among the earliest peoples to use fermentation to brew their own beer.
• The Romans liked to have good sanitation and prized clean drinking water.
• Ancient Chinese immunized people against smallpox by having them inhale dried, powdered scabs from those suffering from a mild form of the disease.
• Many traditional cultures have also recognized and used plants as remedies for certain diseases. For example, South Americans recognized the usefulness of extracts Cinchona tree (containing quinine) to treat malaria. The importance of traditional healers is being rediscovered by the West and has contributed to the field of ethnobotany.
• Many cultures recognized the communicability of certain diseases. Unfortunately, this recognition led to fear of and discrimination against sick people. These fears still persist today.

Pioneer microbiologists:

"The history of science, when done well..does not create heroes to whom we can never measure up and villains who never existed." (J. Strick ASM News. April 1997)

Key figures of the late seventeenth century

Robert Hooke: using a compound microscope described cork cells as "little boxes" that reminded him of the cells used by monks. He also described fungi but his microscope was unable to resolve bacteria.

Anton van Leeuwenhoek: considered by many to be the "Father of Microbiology. Leeuwenhoek was not the first to develop a lens or microscope but was the first to describe LIVING microbes, including bacteria. He accurately described microbes as little "animalcules" in a report to the Royal Society in 1676

(Source:J. Strick ASM News. April 1997).

This long held theory advocated that life could arise spontaneously from nonliving or decomposing matter. For example, many believed that flies could develop directly from rotting meat. In a simple but elegant series of experiments, Francesco Redi was among the first to question abiogenesis. Redi was a natural philosopher who worked in the court of the Medici Grand Duke in Tuscany in the mid 1600's. Redi provided non-microscopic evidence against abiogenesis by showing flies developed from maggots on meat in uncovered jars but not from meat in covered jars. Redi developed an approach crucial to the scientific method; extensive retesting of his results. However, the debate over spontaneous generation would not go away for quite some time.

In the mid 1700's, John Needham, an English clergyman and proponent of abiogenesis, claimed that life arose spontaneously because of a random or chance clumping of "organic" molecules. In 1766 the researcher, Spallanzani, tried to refute Needham's work by heating hay broth after it was sealed in a flask which preventing microbes from entering by air. Microbes could not grow spontaneously from such reheated broth. His findings were not totally accepted as many believed that oxygen was vital to sustain life and if there had not been any in Spallanzani's flasks then "of course nothing would grow."

A key figure in the debate over abiogenesis was Louis Pasteur who conducted his famous experiments using S-shaped flasks in 1859. Air was allowed to enter flasks but the curved necks trapped bacteria and prevented them from contaminating broth that had previously been boiled. Thus, life could not arise spontaneously from broth even in the presence of air. Interestingly, many biologists, including Pasteur, continued to believe that lower animals such as tapeworms arose by spontaneous generation. Henry Bastian of University College Medical School in London. Bastian conducted many experiments that showed microbes could still grow in various broth's that had been boiled for hours. Although his observations were accurate the growth was not due to abiogenesis. The riddle was solved in 1876 when a German botanist, Cohn identified species of Bacillus, common to hay and cheese, that contained heat-resistant endospores. If Pasteur had used these cultures in his flasks the debate over spontaneous generation could have ended up very differently!

Further contributions of Louis Pasteur

• Fermentation: in 1857 Napoleon III requested help to search for the cause of wine spoilage. Pasteur was the first to discover specific biochemical reactions of microbes. He observed that yeast fermented sugar to ethanol and that bacteria oxidized alcohol to acetic acid to cause spoilage.
• Pasteurization: Pasteur developed a heating process used to kill spoilage germs in wine but which preserved flavor. Prior to pasteurization diseases such as TB were also transmitted in milk. In the early 1900's Mycobacterial-contaminated milk was an important source of TB. Pasteurization also eliminates the milk-borne pathogen Brucella.
• Pasteur also made huge contributions to the field of vaccination and immunity (see separate section under this lecture outline).

This theory provided us with knowledge of the causal relationship between microbes and disease and was an outgrowth of the work of numerous scientists and medical professionals including:

• Joseph Lister, a British physician, operating in the mid 1800's, developed antiseptic surgery which included heat-sterilization of instruments and application of phenols to wounds and dressings. The Missouri physician, Joseph Lawrence, named his now famous mouthwash "Listerine."
• Ignatz Semmelweis, an obstetrician, was hired to oversee 2 maternity wards in a Vienna hospital in 1841; one run by midwives and the other by physicians. He noted that deaths due to a streptococcal infection ("childbirth fever") were much higher in the physicians ward as compared to deaths in the midwives ward. In words this was an example of a nosocomial infection. Semmelweis subsequently instituted strict hand-washing procedures for physicians and could be considered the father of infection control. Despite the fact that his observations made him extremely unpopular with physicians, simple improvements in hygiene reduced transmission of childbirth fever by 2/3.

• Robert Koch

In 1876, Koch provided a critical link between microbes and disease when he used a series of postulates to uncover the cause of anthrax. Koch's postulates are still in use today in order to prove the cause of an infectious disease.

Further contributions of Koch

• isolated the bacteria that cause cholera and tuberculosis
• developed tuberculin, now used in a skin test for TB (originally intended for use as a vaccine against TB)
• developed acid-fast staining
• identified bacterial endospores
• with colleagues, the first to grow cultures on solid media
• received noble prize for medicine 1905.

A vaccine is a preparation of microbes or their subunits that is designed to produce immunity to a disease. As mentioned in the introduction, the ancient Chinese were among the earliest cultures to recognize that material from recovering smallpox victims could be used to immunize others. The problem with crude techniques such as these is that they used living organisms for immunizations which could potentially be virulent.

In the late 1700's the British physician, Edward Jenner was told by a milkmaid that she never had to worry about catching smallpox as she had already had cowpox. This observation was backed up by villagers "if you want to marry a woman who will never be scarred by the pox, marry a milkmaid." Jenner demonstrated that inoculation with scrapings from cowpox provided immunity to the more virulent smallpox virus. He used an 8 year old boy called James Phipps to test his vaccine. James was inoculated with virulent matter from cowpox lesions on the fingers of a milkmaid called Sarah Neimes. Phipps developed a mild fever and some cowpox lesions. Several weeks later Phipps was injected with LIVE smallpox (Today we call this a "challenge experiment"). Thankfully, James was protected from the disease. Jenner noted that this immunity was "a change, which endures throughout life."

The type of experiment tried by Jenner is against medical ethics of today. It is not possible to use young children in challenge experiments with live viruses or other microbes.

Due to a massive global eradication/vaccination campaign the last case of naturally occurring smallpox (Ali Maalin) was reported in Somalia in 1977. A hot debate continues over whether or not to destroy the last two stores of smallpox virus.

Louis Pasteur also made large contributions with respect to vaccines. Pasteur found that cholera organisms lost their virulence when passaged in culture. Attenuated (weakened) organisms inoculated into chickens could protect them from virulent strains. Pasteur also developed early vaccines against rabies and anthrax. Ironically, during the course of his work, he lost his father and two sisters to typhoid fever.

Elie Metchnikoff was a Russian researcher and is considered the father of cellular immunity largely for his observations of phagocytosis in sea star larvae. Metchnikoff shared the Nobel Prize for medicine with the German microbiologist, Paul Ehrlich in 1908.

As long as people and microbes have been around people have been looking for a way to treat infectious diseases. Some key figures and events in chemotherapy include:

• Mid 1600's. The British physician, Thomas Sydenham introduces quinine-containing Cinchona bark from South America. Quinine has long been used as an antimalarial
• 1910. Paul Ehrlich. Developed Salvarsan (compound 606) for the treatment of syphilis. Ehrlich worked under Robert Koch. While working on differential staining techniques Ehrlich developed the idea of using a "magic bullet" that would kill disease-causing microbes but spare the host with minimal toxicity.
• 1928. Alexander Fleming observed that penicillium mold inhibited growth of Staphylococci growing on a petri plate. Penicillin became widely available and known as the "wonder-drug" with the advent of world war II. Fleming shared the Nobel prize for his efforts along with the researchers, Florey and Chain. Unfortunately, we are faced with many penicillin resistant microbes today such as MRSA and PPNG (discussed in lecture on drug resistance.)
• 1930's. Domagk develops sulfa drugs. These drugs are especially useful in treating urinary tract infections and are used in combination formulas to prevent pneumocystis pneumonia.
• 1952. Selman Waksman isolates streptomycin. This antibiotic was the first effective drug available to treat infections with gram negative bacteria and tuberculosis.
• 1987. AZT becomes the first drug licensed for treating HIV disease. This was the same year that President Reagan made his first public mention of AIDS. By that time, 25,000 Americans had already died of AIDS and countless others overseas. The first cases of AIDS in the U.S. were reported in 1981.
• 1995. First generation of drugs called protease inhibitors are approved to help treat HIV disease. These drugs continue to extend an improve the quality of life for many recipients. However, there is a constant threat of drug resistance and the majority of HIV+ people around the world do NOT and WILL NOT have access to these drugs!

A common theme in the history of battling infectious diseases is that people tend go through a "honeymoon period" each time an exciting new drug appears on the market. However, it is not realistic to believe that any given drug will be the cure-all and more often than not we will have to live with the idea of CONTROL versus ERADICATION of certain diseases.