World of Microbiology and Immunology vol 1 - part 4 pdf

See also Bacterial growth and division; Chemoautotrophic and chemolithotrophic bacteria; Metabolism; Methane oxidiz-ing and producoxidiz-ing bacteria; Nitrogen cycle in microorganisms Ca

Cech, Thomas R.

Both types of conversion take place in the presence andthe absence of oxygen Algal involvement is an aerobic

process The conversion of carbon dioxide to sugar is an

energy-requiring process that generates oxygen as a

by-prod-uct This evolutionof oxygen also occurs in plants and is one

of the recognized vital benefits of trees to life on Earth

The carbon available in the carbohydrate sugar cules is cycled further by microorganisms in a series of reac-

mole-tions that form the so-called tricarboxylic acid (or TCA) cycle

The breakdown of the carbohydrate serves to supply energy to

the microorganism This process is also known as respiration

In anaerobic environments, microorganisms can cycle the

car-bon compounds to yield energy in a process known as

fer-mentation

Carbon dioxide can be converted to another gas calledmethane (CH4) This occurs in anaerobic environments, such

as deep compacted mud, and is accomplished by bacteria

known as methanogenic bacteria The conversion, which

requires hydrogen, yields water and energy for the

methanogens To complete the recycling pattern another group

of methane bacteria called methane-oxidizing bacteria or

methanotrophs (literally “methane eaters”) can convert

methane to carbon dioxide This conversion, which is an

aer-obic (oxygen-requiring) process, also yields water and energy

Methanotrophs tend to live at the boundary between aerobic

and anaerobic zones There they have access to the methane

produced by the anaerobic methanogenic bacteria, but also

access to the oxygen needed for their conversion of the

methane

Other microorganisms are able to participate in thecycling of carbon For example the green and purple sulfur

bacteria are able to use the energy they gain from the

degra-dation of a compound called hydrogen sulfide to degrade

car-bon compounds Other bacteria such as Thiobacillus

ferrooxidans uses the energy gained from the removal of an

electron from iron-containing compounds to convert carbon

The anerobic degradation of carbon is done only bymicroorganisms This degradation is a collaborative effort

involving numerous bacteria Examples of the bacteria include

Bacteroides succinogenes, Clostridium butyricum, and

Syntrophomonas sp This bacterial collaboration, which is

termed interspecies hydrogen transfer, is responsible for the

bulk of the carbon dioxide and methane that is released to the

atmosphere

See also Bacterial growth and division; Chemoautotrophic

and chemolithotrophic bacteria; Metabolism; Methane

oxidiz-ing and producoxidiz-ing bacteria; Nitrogen cycle in microorganisms

Caulobacter

Caulobacter crescentus is a Gram-negative rod-like bacterium

that inhabits fresh water It is noteworthy principally because

of the unusual nature of its division Instead of dividing two

form two identical daughter cells as other bacteria do (a

process termed binary division), Caulobacter crescentus

undergoes what is termed symmetric division The parent

bac-terium divides to yield two daughter cells that differ from oneanother structurally and functionally

When a bacterium divides, one cell is motile by virtue of

a single flagellum at one end This daughter cell is called aswarmer cell The other cell does not have a flagellum Instead,

at one end of the cell there is a stalk that terminates in anattachment structure called a holdfast This daughter cell iscalled the stalk cell The stalk is an outgrowth of the cell wall,and serves to attach the bacterium to plants or to other microbes

in its natural environment (lakes, streams, and sea water)

Caulobacter crescentus exhibits a distinctive behavior.

The swarmer cell remains motile for 30 to 45 minutes The cellswims around and settles onto a new surface where the foodsupply is suitable After settling, the flagellum is shed and thebacterium differentiates into a stalk cell With each divisioncycle the stalk becomes longer and can grow to be severaltimes as long as the body of the bacterium

The regulation of gene expression is different in theswarmer and stalk cells Replication of the genetic materialoccurs immediately in the stalk cell but for reasons yet to bedetermined is repressed in the swarmer cell However, when aswarmer cell differentiates into a stalk cell, replication of thegenetic material immediately commences Thus, the transition

to a stalk cell is necessary before division into the daughterswarmer and stalk cells can occur

The genetics of the swarmer to stalk cell cycleare plex, with at least 500 genes known to play a role in the struc-tural transition The regulation of these activities with respect

com-to time are of great interest com-to geneticists

Caulobacter crescentus can be grown in the laboratory

so that all the bacteria in the population undergoes division atthe same time This type of growth is termed synchronous growth This has made the bacterium an ideal system to studythe various events in gene regulation necessary for growth anddivision

See also Bacterial appendages; Bacterial surface layers; Cell

cycle (prokaryotic), genetic regulation of; Phenotypic variation

CDC • see CENTERS FORDISEASECONTROL(CDC)

Cech, Thomas R • WORLD OF MICROBIOLOGY AND IMMUNOLOGY

separate—that there was a delicate division of labor Cech and

his colleagues at the University of Colorado established,

how-ever, that this picture of how RNA functions was incorrect;

they proved that in the absence of other enzymes RNA acts as

its own catalyst It was a discovery that reverberated

through-out the scientific community, leading not only to new

tech-nologies in RNA engineering but also to a revised view of the

evolution of life Cech shared the 1989 Nobel Prize for

Chemistry with Sidney Altman at Yale University for their

work regarding the role of RNA in cell reactions

Cech was born in Chicago, Illinois, to Robert FranklinCech, a physician, and Annette Marie Cerveny Cech Cech

recalled in an autobiographical sketch for Les Prix Nobel, he

grew up in “the safe streets and good schools” of Iowa City,

Iowa His father had a deep and abiding interest in physics as

well as medicine, and from an early age Cech took an avid

inter-est in science, collecting rocks and minerals and speculating

about how they had been formed In junior high school he was

already conferring with geology professors from the nearby

uni-versity Cech went to Grinnell College in 1966; at first attracted

to physical chemistry, he soon concentrated on biological

chem-istry, graduating with a chemistry degree in 1970

It was at Grinnell that he met Carol Lynn Martinson,who was a fellow chemistry student They married in 1970 and

went together to the University of California at Berkeley for

graduate studies His thesis advisor there was John Hearst who,

Cech recalled in Les Prix Nobel, “had an enthusiasm for

chro-mosome structure and function that proved infectious.” Both

Cech and his wife were awarded their Ph.D degrees in 1975,

and they moved to the east coast for postdoctoral positions—

Cech at the Massachusetts Institute of Technology (MIT) under

Mary Lou Pardue, and his wife at Harvard At MIT Cech

focused on the DNA structures of the mouse genome,

strength-ening his knowledge of biology at the same time

In 1978, both Cech and his wife were offered positions

at the University of Colorado in Boulder; he was appointed

assistant professor in chemistry By this time, Cech had

decided that he would like to investigate more specific genetic

material He was particularly interested in what enables the

DNA molecule to instruct the body to produce the various

parts of itself—a process known as geneexpression Cech set

out to discover the proteins that govern the DNAtranscription

process onto RNA, and in order to do this he decided to use

nucleic acids from a single-cell protozoa, Tetrahymena

ther-mophila Cech chose Tetrahymena because it rapidly

repro-duced genetic material and because it had a structure which

allowed for the easy extraction of DNA

By the late 1970s, much research had already been done

on DNA and its transcription partner, RNA It had been

deter-mined that there were three types of RNA: messenger RNA,

which relays the transcription of the DNA structure by

attach-ing itself to the ribosome where protein synthesisoccurs;

ribo-somal RNA, which imparts the messenger’s structure within

the ribosome; and transfer RNA, which helps to establish

amino acids in the proper order in the protein chain as it is

being built Just prior to the time Cech began his work, it was

discovered that DNA and final-product RNA (after copying or

transcription) actually differed In 1977, Phillip A Sharp and

others discovered that portions of seemingly noncoded DNAwere snipped out of the RNA and the chain was spliced backtogether where these intervening segments had been removed.These noncoded sections of DNA were called introns.Cech and his coworkers were not initially interested insuch introns, but they soon became fascinated with their func-tion and the splicing mechanism itself In an effort to understandhow these so-called nonsense sequences, or introns, wereremoved from the transcribed RNA, Cech and his colleagueArthur Zaug decided to investigate the pre-ribosomal RNA of

the Tetrahymena, just as it underwent transcription In order to

do this, they first isolated unspliced RNA and then added some

Tetrahymena nuclei extract Their assumption was that the

cat-alytic agent or enzyme would be present in such an extract Thetwo scientists also added small molecules of salts andnucleotides for energy, varying the amounts of each in subse-quent experiments, even excluding one or more of the additives.But the experiment took a different turn than was expected.Cech and Zaug discovered instead that RNA splicingoccurred even without the nucleic material being present Thiswas a development they did not understand at first; it was along-held scientific belief that proteins in the form of enzymeshad to be present for catalysis to occur Presenting itself was asituation in which RNA appeared to be its own catalytic moti-vator At first they suspected that their experiment had beencontaminated Cech did further experiments involving recom-binant DNA in which there could be no possibility of the pres-ence of splicing enzymes, and these had the same result: theRNA spliced out its own intron Further discoveries in Cech’slaboratory into the nature of the intron led to his belief that theintron itself was the catalytic agent of RNA splicing, and hedecided that this was a sort of RNA enzyme which they calledthe ribozyme

Cech’s findings of 1982 met with heated debate in thescientific community, for it upset many beliefs about thenature of enzymes Cech’s ribozyme was in fact not a trueenzyme, for thus far he had shown it only to work upon itselfand to be changed in the reaction; true enzymes catalyzerepeatedly and come out of the reaction unchanged Other crit-ics argued that this was a freak bit of RNA on a strangemicroorganism and that it would not be found in other organ-isms The critics were soon proved wrong, however, when sci-entists around the world began discovering other RNAenzymes In 1984, Sidney Altman proved that RNA carries outenzyme-like activities on substances other than itself

The discovery of catalytic RNA has had profoundresults In the medical field alone RNA enzymology may lead

to cures of viral infections By using these rybozymes as genescissors, the RNA molecule can be cut at certain points,destroying the RNA molecules that cause infections or geneticdisorders In life sciences, the discovery of catalytic RNA hasalso changed conventional wisdom The old debate aboutwhether proteins or nucleic acids were the first bit of life formseems to have been solved If RNA can act as a catalyst and agenetic template to create proteins as well as itself, then it israther certain that RNA was first in the chain of life

Cech and Altman won the Nobel Prize for chemistry in

1989 for their independent discoveries of catalytic RNA Cech

Cell cycle and cell division

has also been awarded the Passano Foundation Young

Scientist Award and the Harrison Howe Award in 1984; the

Pfizer Award in Enzyme Chemistry in 1985; the U S Steel

Award in Molecular Biology; and the V D Mattia Award in

1987 In 1988, he won the Newcombe-Cleveland Award, the

Heineken Prize, the Gairdner Foundation International Award,

the Louisa Gross Horwitz Prize, and the Albert Lasker Basic

Medical Research Award; he was presented with the

Bonfils-Stanton Award for Science in 1990

Cech was made full professor in the department ofchemistry at the University of Colorado in 1983 Cech and his

wife have two daughters In the midst of his busy research

career, Cech finds time to enjoy skiing and backpacking

See also Viral genetics

IMMUNITY, CELL MEDIATED

Cell cycle and cell division

The series of stages that a cell undergoes while progressing to

division is known as cell cycle In order for an organism to

grow and develop, the organism’s cells must be able to

dupli-cate themselves Three basic events must take place to achieve

this duplication: the deoxyribonucleic acid DNA, which makes

up the individual chromosomeswithin the cell’s nucleusmust

be duplicated; the two sets of DNA must be packaged up into

two separate nuclei; and the cell’s cytoplasmmust divide itself

to create two separate cells, each complete with its own

nucleus The two new cells, products of the single original

cell, are known as daughter cells

Although prokaryotes (e.g bacteria, non-nucleated cellular organisms) divide through binary fission, eukaryotes

uni-(including, of course, human cells) undergo a more complex

process of cell division because DNA is packed in several

chromosomes located inside a cell nucleus In eukaryotes, cell

division may take two different paths, in accordance with the

cell type involved Mitosis is a cellular division resulting in

two identical nuclei that takes place in somatic cells Sex cells

or gametes (ovum and spermatozoids) divide by meiosis The

process of meiosis results in four nuclei, each containing half

of the original number of chromosomes Both prokaryotes and

eukaryotes undergo a final process, known as cytoplasmatic

division, which divides the parental cell in new daughter cells

Mitosis is the process during which two complete,identical sets of chromosomes are produced from one origi-

nal set This allows a cell to divide during another process

called cytokinesis, thus creating two completely identical

daughter cells

During much of a cell’s life, the DNA within the nucleus

is not actually organized into the discrete units known as

chro-mosomes Instead, the DNA exists loosely within the nucleus,

in a form called chromatin Prior to the major events of

mito-sis, the DNA must replicate itself, so that each cell has twice

as much DNA as previously

Cells undergoing division are also termed competentcells When a cell is not progressing to mitosis, it remains inphase G0 (“G” zero) Therefore, the cell cycle is divided intotwo major phases: interphase and mitosis Interphase includesthe phases (or stages) G1, S and G2 whereas mitosis is subdi-vided into prophase, metaphase, anaphase and telophase.Interphase is a phase of cell growth and metabolic activ-ity, without cell nuclear division, comprised of several stages

or phases During Gap 1 or G1 the cell resumes protein and

RNAsynthesis, which was interrupted during previous mitosis,thus allowing the growth and maturation of young cells toaccomplish their physiologic function Immediately following

is a variable length pause for DNA checking and repair beforecell cycle transition to phase S during which there is synthesis

or semi-conservative replication or synthesis of DNA DuringGap 2 or G2, there is increased RNA and protein synthesis,followed by a second pause for proofreading and eventualrepairs in the newly synthesized DNA sequences before tran-sition to mitosis

The cell cycle starts in G1, with the active synthesis ofRNA and proteins, which are necessary for young cells to growand mature The time G1 lasts, varies greatly among eukaryoticcells of different species and from one tissue to another in thesame organism Tissues that require fast cellular renovation,such as mucosa and endometrial epithelia, have shorter G1periods than those tissues that do not require frequent renova-tion or repair, such as muscles or connective tissues

The first stage of mitosis is called prophase Duringprophase, the DNA organizes or condenses itself into the spe-cific units known as chromosomes Chromosomes appear asdouble-stranded structures Each strand is a replica of theother and is called a chromatid The two chromatids of a chro-mosome are joined at a special region, the centromere.Structures called centrioles position themselves across fromeach other, at either end of the cell The nuclear membranethen disappears

During the stage of mitosis called metaphase, the mosomes line themselves up along the midline of the cell.Fibers called spindles attach themselves to the centromere ofeach chromosome

chro-During the third stage of mitosis, called anaphase, dle fibers will pull the chromosomes apart at their centromere(chromosomes have two complementary halves, similar to thetwo nonidentical but complementary halves of a zipper) Onearm of each chromosome will migrate toward each centriole,pulled by the spindle fibers

spin-During the final stage of mitosis, telophase, the mosomes decondense, becoming unorganized chromatinagain A nuclear membrane forms around each daughter set ofchromosomes, and the spindle fibers disappear Sometimeduring telophase, the cytoplasm and cytoplasmic membrane ofthe cell split into two (cytokinesis), each containing one set ofchromosomes residing within its nucleus

chro-Cells are mainly induced into proliferation by growthfactors or hormones that occupy specific receptors on the sur-face of the cell membrane, being also known as extra-cellular

Cell cycle and cell division • WORLD OF MICROBIOLOGY AND IMMUNOLOGY

ligands Examples of growth factors are as such: epidermal

growth factor (EGF), fibroblastic growth factor (FGF),

platelet-derived growth factor (PDGF), insulin-like growth

factor (IGF), or by hormones PDGF and FGF act by

regulat-ing the phase G2 of the cell cycle and durregulat-ing mitosis After

mitosis, they act again stimulating the daughter cells to grow,

thus leading them from G0 to G1 Therefore, FGF and PDGF

are also termed competence factors, whereas EGF and IGF are

termed progression factors, because they keep the process of

cellular progression to mitosis going on Growth factors are

also classified (along with other molecules that promote the

cell cycle) as mitotic signals Hormones are also

pro-mitotic signals For example, thyrotrophic hormone, one of the

hormones produced by the pituitary gland, induces the

prolif-eration of thyroid gland’s cells Another pituitary hormone,

known as growth hormone or somatotrophic hormone (STH),

is responsible by body growth during childhood and early

ado-lescence, inducing the lengthening of the long bones and

pro-tein synthesis Estrogens are hormones that do not occupy a

membrane receptor, but instead, penetrate the cell and the

nucleus, binding directly to specific sites in the DNA, thus

inducing the cell cycle

Anti-mitotic signals may have several different origins,such as cell-to-cell adhesion, factors of adhesion to the extra-

cellular matrix, or soluble factor such as TGF beta (tumor

growth factor beta), which inhibits abnormal cell proliferation,

proteins p53, p16, p21, APC, pRb, etc These molecules are

the products of a class of genes called tumor suppressor genes

Oncogenes, until recently also known as proto-oncogenes,

synthesize proteins that enhance the stimuli started by growth

factors, amplifying the mitotic signal to the nucleus, and/or

promoting the accomplishment of a necessary step of the cell

cycle When each phase of the cell cycle is completed, the

pro-teins involved in that phase are degraded, so that once the nextphase starts, the cell is unable to go back to the previous one.Next to the end of phase G1, the cycle is paused by tumor sup-pressor gene products, to allow verification and repair ofDNA damage When DNA damage is not repairable, thesegenes stimulate other intra-cellular pathways that induce thecell into suicide or apoptosis (also known as programmed celldeath) To the end of phase G2, before the transition to mito-sis, the cycle is paused again for a new verification and “deci-sion”: either mitosis or apoptosis

Along each pro-mitotic and anti-mitotic intra-cellular naling pathway, as well as along the apoptotic pathways, severalgene products (proteins and enzymes) are involved in anorderly sequence of activation and inactivation, forming com-plex webs of signal transmission and signal amplification to thenucleus The general goal of such cascades of signals is toachieve the orderly progression of each phase of the cell cycle.Mitosis always creates two completely identical cellsfrom the original cell In mitosis, the total amount of DNAdoubles briefly, so that the subsequent daughter cells will ulti-mately have the exact amount of DNA initially present in theoriginal cell Mitosis is the process by which all of the cells ofthe body divide and therefore reproduce The only cells of thebody that do not duplicate through mitosis are the sex cells(egg and sperm cells) These cells undergo a slightly differenttype of cell division called meiosis, which allows each sex cellproduced to contain half of its original amount of DNA, inanticipation of doubling it again when an egg and a spermunite during the course of conception

sig-Meiosis, also known as reduction division, consists oftwo successive cell divisions in diploid cells The two celldivisions are similar to mitosis, but differ in that the chromo-somes are duplicated only once, not twice The result of meio-sis is four haploid daughter cells Because meiosis only occurs

in the sex organs (gonads), the daughter cells are the gametes(spermatozoa or ova), which contain hereditary material Byhalving the number of chromosomes in the sex cells, meiosisassures that the fusion of maternal and paternal gametes at fer-tilization will result in offspring with the same chromosomenumber as the parents In other words, meiosis compensatesfor chromosomes doubling at fertilization The two successivenuclear divisions are termed as meiosis I and meiosis II Each

is further divided into four phases (prophase, metaphase,anaphase, and telophase) with an intermediate phase (inter-phase) preceding each nuclear division

The events that take place during meiosis are similar inmany ways to the process of mitosis, in which one cell divides

to form two clones (exact copies) of itself It is important tonote that the purpose and final products of mitosis and meio-sis are very different

Meiosis I is preceded by an interphase period in whichthe DNA replicates (makes an exact duplicate of itself), result-ing in two exact copies of each chromosome that are firmlyattached at one point, the centromere Each copy is a sisterchromatid, and the pair are still considered as only one chro-mosome The first phase of meiosis I, prophase I, begins as thechromosomes come together in homologous pairs in a processknown as synapsis Homologous chromosomes, or homo-

Segregation of eukaryotic genetic material during mitosis.

Cell cycle and cell division

logues, consist of two chromosomes that carry genetic

infor-mation for the same traits, although that inforinfor-mation may hold

different messages (e.g., when two chromosomes carry a

mes-sage for eye color, but one codes for blue eyes while the other

codes for brown) The fertilized eggs (zygotes) of all sexually

reproducing organisms receive their chromosomes in pairs,

one from the mother and one from the father During synapsis,

adjacent chromatids from homologous chromosomes “cross

over” one another at random points and join at spots called

chiasmata These connections hold the pair together as a tetrad

(a set of four chromatids, two from each homologue) At the

chiasmata, the connected chromatids randomly exchange bits

of genetic information so that each contains a mixture of

maternal and paternal genes This “shuffling” of the DNA

pro-duces a tetrad, in which each of the chromatids is different

from the others, and a gamete that is different from others

pro-duced by the same parent Crossing over does explain why

each person is a unique individual, different even from those

in the immediate family Prophase I is also marked by the

appearance of spindle fibers (strands of microtubules)

extend-ing from the poles or ends of the cell as the nuclear membrane

disappears These spindle fibers attach to the chromosomes

during metaphase I as the tetrads line up along the middle or

equator of the cell A spindle fiber from one pole attaches to

one chromosome while a fiber from the opposite pole attaches

to its homologue Anaphase I is characterized by the

separa-tion of the homologues, as chromosomes are drawn to the

opposite poles The sister chromatids are still intact, but the

homologous chromosomes are pulled apart at the chiasmata

Telophase I begins as the chromosomes reach the poles and a

nuclear membrane forms around each set Cytokinesis occurs

as the cytoplasm and organelles are divided in half and the one

parent cell is split into two new daughter cells Each daughter

cell is now haploid (n), meaning it has half the number of

chromosomes of the original parent cell (which is diploid-2n)

These chromosomes in the daughter cells still exist as sister

chromatids, but there is only one chromosome from each

orig-inal homologous pair

The phases of meiosis II are similar to those of meiosis

I, but there are some important differences The time between

the two nuclear divisions (interphase II) lacks replication of

DNA (as in interphase I) As the two daughter cells produced

in meiosis I enter meiosis II, their chromosomes are in the

form of sister chromatids No crossing over occurs in prophase

II because there are no homologues to synapse During

metaphase II, the spindle fibers from the opposite poles attach

to the sister chromatids (instead of the homologues as before)

The chromatids are then pulled apart during anaphase II As

the centromeres separate, the two single chromosomes are

drawn to the opposite poles The end result of meiosis II is that

by the end of telophase II, there are four haploid daughter cells

(in the sperm or ova) with each chromosome now represented

by a single copy The distribution of chromatids during

meio-sis is a matter of chance, which results in the concept of the

law of independent assortment in genetics

The events of meiosis are controlled by a proteinenzyme complex known collectively as maturation promoting

factor (MPF) These enzymesinteract with one another and

with cell organelles to cause the breakdown and reconstruction

of the nuclear membrane, the formation of the spindle fibers,and the final division of the cell itself MPF appears to work

in a cycle, with the proteins slowly accumulating during phase, and then rapidly degrading during the later stages ofmeiosis In effect, the rate of synthesis of these proteins con-trols the frequency and rate of meiosis in all sexually repro-ducing organisms from the simplest to the most complex.Meiosis occurs in humans, giving rise to the haploidgametes, the sperm and egg cells In males, the process ofgamete production is known as spermatogenesis, where eachdividing cell in the testes produces four functional sperm cells,all approximately the same size Each is propelled by a prim-itive but highly efficient flagellum (tail) In contrast, infemales, oogenesis produces only one surviving egg cell fromeach original parent cell During cytokinesis, the cytoplasmand organelles are concentrated into only one of the fourdaughter cells—the one that will eventually become thefemale ovum or egg The other three smaller cells, called polarbodies, die and are reabsorbed shortly after formation Theconcentration of cytoplasm and organelles into the oocytegreatly enhances the ability of the zygote (produced at fertil-ization from the unification of the mature ovum with a sper-matozoa) to undergo rapid cell division

inter-The control of cell division is a complex process and is

a topic of much scientific research Cell division is stimulated

by certain kinds of chemical compounds Molecules called

cytokines are secreted by some cells to stimulate others tobegin cell division Contact with adjacent cells can also con-trol cell division The phenomenon of contact inhibition is aprocess where the physical contact between neighboring cellsprevents cell division from occurring When contact is inter-rupted, however, cell division is stimulated to close the gapbetween cells Cell division is a major mechanism by whichorganisms grow, tissues and organs maintain themselves, andwound healing occurs

Cancer is a form of uncontrolled cell division The cellcycle is highly regulated by several enzymes, proteins, andcytokines in each of its phases, in order to ensure that theresulting daughter cells receive the appropriate amount ofgenetic information originally present in the parental cell Inthe case of somatic cells, each of the two daughter cells mustcontain an exact copy of the original genome present in theparental cell Cell cycle controls also regulate when and towhat extent the cells of a given tissue must proliferate, in order

to avoid abnormal cell proliferation that could lead to sia or tumor development Therefore, when one or more ofsuch controls are lost or inhibited, abnormal overgrowth willoccur and may lead to impairment of function and disease

dyspla-See also Amino acid chemistry; Bacterial growth and division;

Cell cycle (eukaryotic), genetic regulation of; Cell cycle(prokaryotic), genetic regulation of; Chromosomes, eukary-otic; Chromosomes, prokaryotic; DNA (Deoxyribonucleicacid); Enzymes; Genetic regulation of eukaryotic cells;Genetic regulation of prokaryotic cells; Molecular biology andmolecular genetics

Cell cycle (eukaryotic), genetic regulation of • WORLD OF MICROBIOLOGY AND IMMUNOLOGY

REGULATION OF

Cell cycle (eukaryotic), genetic regulation of

Although prokaryotes (i.e., non-nucleated unicellular

organ-isms) divide through binary fission, eukaryotes undergo a

more complex process of cell division because DNAis packed

in several chromosomes located inside a cell nucleus In

eukaryotes, cell division may take two different paths, in

accordance with the cell type involved Mitosis is a cellular

division resulting in two identical nuclei is performed by

somatic cells The process of meiosis results in four nuclei,

each containing half of the original number of chromosomes

Sex cells or gametes (ovum and spermatozoids) divide by

meiosis Both prokaryotes and eukaryotes undergo a final

process, known as cytoplasmatic division, which divides the

parental cell into new daughter cells

The series of stages that a cell undergoes while gressing to division is known as cell cycle Cells undergoing

pro-division are also termed competent cells When a cell is not

progressing to mitosis, it remains in phase G0 (“G” zero)

Therefore, the cell cycle is divided into two major phases:

interphase and mitosis Interphase includes the phases (or

stages) G1, S and G2 whereas mitosis is subdivided into

prophase, metaphase, anaphase and telophase

The cell cycle starts in G1, with the active synthesis of

RNAand proteins, which are necessary for young cells to grow

and mature The time G1 lasts, varies greatly among

eukary-otic cells of different species and from one tissue to another in

the same organism Tissues that require fast cellular

renova-tion, such as mucosa and endometrial epithelia, have shorter

G1 periods than those tissues that do not require frequent

ren-ovation or repair, such as muscles or connective tissues

The cell cycle is highly regulated by several enzymes,proteins, and cytokinesin each of its phases, in order to ensure

that the resulting daughter cells receive the appropriate amount

of genetic information originally present in the parental cell In

the case of somatic cells, each of the two daughter cells must

contain an exact copy of the original genome present in the

parental cell Cell cycle controls also regulate when and to what

extent the cells of a given tissue must proliferate, in order to

avoid abnormal cell proliferation that could lead to dysplasia or

tumor development Therefore, when one or more of such

con-trols are lost or inhibited, abnormal overgrowth will occur and

may lead to impairment of function and disease

Cells are mainly induced into proliferation by growth tors or hormones that occupy specific receptors on the surface

fac-of the cell membrane, and are also known as extra-cellular

lig-ands Examples of growth factors are as such: epidermal growth

factor (EGF), fibroblastic growth factor (FGF), platelet-derived

growth factor (PDGF), insulin-like growth factor (IGF), or by

hormones PDGF and FGF act by regulating the phase G2 of the

cell cycle and during mitosis After mitosis, they act again

stim-ulating the daughter cells to grow, thus leading them from G0 to

G1 Therefore, FGF and PDGF are also termed competence

fac-tors, whereas EGF and IGF are termed progression facfac-tors,

because they keep the process of cellular progression to mitosis

going on Growth factors are also classified (along with other

molecules that promote the cell cycle) as pro-mitotic signals.Hormones are also pro-mitotic signals For example, thy-rotrophic hormone, one of the hormones produced by the pitu-itary gland, induces the proliferation of thyroid gland’s cells.Another pituitary hormone, known as growth hormone or soma-totrophic hormone (STH), is responsible by body growth duringchildhood and early adolescence, inducing the lengthening ofthe long bones and protein synthesis Estrogens are hormonesthat do not occupy a membrane receptor, but instead, penetratethe cell and the nucleus, binding directly to specific sites in theDNA, thus inducing the cell cycle

Anti-mitotic signals may have several different origins,such as cell-to-cell adhesion, factors of adhesion to the extra-cellular matrix, or soluble factor such as TGF beta (tumorgrowth factor beta), which inhibits abnormal cell proliferation,proteins p53, p16, p21, APC, pRb, etc These molecules arethe products of a class of genes called tumor suppressor genes.Oncogenes, until recently also known as proto-oncogenes,synthesize proteins that enhance the stimuli started by growthfactors, amplifying the mitotic signal to the nucleus, and/orpromoting the accomplishment of a necessary step of the cellcycle When each phase of the cell cycle is completed, the pro-teins involved in that phase are degraded, so that once the nextphase starts, the cell is unable to go back to the previous one.Next to the end of phase G1, the cycle is paused by tumor sup-pressor gene products, to allow verification and repair ofDNA damage When DNA damage is not repairable, thesegenes stimulate other intra-cellular pathways that induce thecell into suicide or apoptosis (also known as programmed celldeath) To the end of phase G2, before the transition to mito-sis, the cycle is paused again for a new verification and “deci-sion”: either mitosis or apoptosis

Along each pro-mitotic and anti-mitotic intra-cellular naling pathway, as well as along the apoptotic pathways, severalgene products (proteins and enzymes) are involved in anorderly sequence of activation and inactivation, forming com-plex webs of signal transmission and signal amplification to thenucleus The general goal of such cascades of signals is toachieve the orderly progression of each phase of the cell cycle.Interphase is a phase of cell growth and metabolic activ-ity, without cell nuclear division, comprised of several stages orphases During Gap 1 or G1 the cell resumes protein and RNAsynthesis, which was interrupted during mitosis, thus allowingthe growth and maturation of young cells to accomplish theirphysiologic function Immediately following is a variablelength pause for DNA checking and repair before cell cycletransition to phase S during which there is synthesis or semi-conservative replication or synthesis of DNA During Gap 2 orG2, there is increased RNA and protein synthesis, followed by

sig-a second psig-ause for proofresig-ading sig-and eventusig-al repsig-airs in thenewly synthesized DNA sequences before transition to Mitosis

At the start of mitosis the chromosomes are alreadyduplicated, with the sister-chromatids (identical chromo-somes) clearly visible under a light microscope Mitosis issubdivided into prophase, metaphase, anaphase and telophase.During prophase there is a high condensation of chro-matids, with the beginning of nucleolus disorganization andnuclear membrane disintegration, followed by the start of cen-

Cell cycle (eukaryotic), genetic regulation of

trioles’ migration to opposite cell poles During metaphase the

chromosomes organize at the equator of a spindle apparatus

(microtubules), forming a structure termed metaphase plate

The sister-chromatids are separated and joined to different

centromeres, while the microtubules forming the spindle are

attached to a region of the centromere termed kinetochore

During anaphase there are spindles, running from each

oppo-site kinetochore, that pull each set of chromosomes to their

respective cell poles, thus ensuring that in the following phase

each new cell will ultimately receive an equal division of mosomes During telophase, kinetochores and spindles disin-tegrate, the reorganization of nucleus begins, chromatinbecomes less condensed, and the nucleus membrane startforming again around each set of chromosomes Thecytoskeleton is reorganized and the somatic cell has now dou-bled its volume and presents two organized nucleus

chro-Cytokinesis usually begins during telophase, and is theprocess of cytoplasmatic division This process of division

Scanning electron micrograph of eukaryotic cell division.

Cell cycle (prokaryotic), genetic regulation of • WORLD OF MICROBIOLOGY AND IMMUNOLOGY

varies among species but in somatic cells, it occurs through

the equal division of the cytoplasmatic content, with the

plasma membrane forming inwardly a deep cleft that

ulti-mately divides the parental cell in two new daughter cells

The identification and detailed understanding of themany molecules involved in the cell cycle controls and intra-

cellular signal transductionis presently under investigation by

several research groups around the world This knowledge is

crucial to the development of new anti-cancer drugs as well as

to new treatments for other genetic diseases, in which a gene

over expression or deregulation may be causing either a

chronic or an acute disease, or the impairment of a vital organ

function Scientists predict that the next two decades will be

dedicated to the identification of gene products and their

respective function in the cellular microenvironment This

new field of research is termed proteomics

See also Cell cycle (Prokaryotic) genetic regulation of;

Genetic regulation of eukaryotic cells; Genetic regulation of

prokaryotic cells

REGULATION OF

Cell cycle (prokaryotic), genetic regulation of

Although prokaryotes do not have an organized nucleusand

other complex organelles found in eukaryotic cells,

prokary-otic organisms share some common features with eukaryotes

as far as cell division is concerned For example, they both

replicate DNAin a semi conservative manner, and the

segrega-tion of the newly formed DNA molecules occurs before the

cell division takes place through cytokinesis Despite such

similarities, the prokaryotic genome is stored in a single DNA

molecule, whereas eukaryotes may contain a varied number of

DNA molecules, specific to each species, seen in the

interpha-sic nucleus as chromosomes Prokaryotic cells also differ in

other ways from eukaryotic cells Prokaryotes do not have

cytoskeleton and the DNA is not condensed during mitosis

The prokaryote chromosomes do not present histones, the

complexes of histonic proteins that help to pack eukaryotic

DNA into a condensate state Prokaryotic DNA has one single

promoter site that initiates replication, whereas eukaryotic

DNA has multiple promoter sites Prokaryotes have a lack of

spindle apparatus (or microtubules), which are essential

struc-tures for chromosome segregation in eukaryotic cells In

prokaryotes, there are no membranes and organelles dividing

the cytosol in different compartments Although two or more

DNA molecules may be present in a given prokaryotic cell,

they are genetically identical They may contain one extra

cir-cular strand of genes known as plasmid, much smaller than the

genomic DNA, and plasmidsmay be transferred to another

prokaryote through bacterial conjugation, a process known as

horizontal genetransfer

The prokaryotic method of reproduction is asexual and

is termed binary fission because one cell is divided in two new

identical cells Some prokaryotes also have a plasmid Genes

in plasmidsare extra-chromosomal genes and can either be

separately duplicated by a class of gene known as posons Type II, or simply passed on to another individual.Transposons Type I may transfer and insert one or more genesfrom the plasmid to the cell DNA or vice-versa causing muta-tion through genetic recombination The chromosome isattached to a region of the internal side of the membrane,forming a nucleoide Some bacterial cells do present two ormore nucleoides, but the genes they contain are identical.The prokaryotic cell cycleis usually a fast process andmay occur every 20 minutes in favorable conditions.However, some bacteria, such as Mycobacterium leprae (the

trans-cause of leprosy), take 12 days to accomplish replication inthe host’s leprous lesion Replication of prokaryotic DNA, aswell as of eukaryotic DNA, is a semi- conservative process,which means that each newly synthesized strand is paired withits complementary parental strand Each daughter cell, there-fore, receives a double-stranded circular DNA molecule that isformed by a new strand is paired with an old strand

The cell cycle is regulated by genes encoding products(i.e., enzymesand proteins) that play crucial roles in the main-tenance of an orderly sequence of events that ensures that eachresultant daughter cell will inherit the same amount of geneticinformation Cell induction into proliferation and DNA repli-cation are controlled by specific gene products, such asenzyme DNA polymerase III, that binds to a promoter region

in the circular DNA, initiating its replication However, DNApolymerase requires the presence of a pre-existing strand ofDNA, which serves as a template, as well as RNAprimers, toinitiate the polymerization of a new strand Before replicationstarts, timidine-H3, (a DNA precursor) is added to a Y-shapedsite where the double helices were separated, known as thereplicating fork The DNA strands are separated by enzymehelicases and kept apart during replication by single strandproteins (or ss DNA-binding proteins) that binds to DNA,while the enzyme topoisomerase further unwinds and elon-gates the two strands to undo the circular ring

DNA polymerase always makes the new strand by ing from the extremity 5’ and terminating at the extremity 3’.Moreover, the two DNA strands have opposite directions (i.e.,they keep an anti-parallel arrangement to each other).Therefore, the new strand 5’ to 3’ that is complementary to theold strand 3’ to 5’ is synthesized in a continuous process (lead-ing strand synthesis), whereas the other new strand (3’ to 5’)

start-is synthesized in several start-isolated fragments (lagging strandsynthesis) that will be later bound together to form the wholestrand The new 3’ to 5’ strand is complementary to the old 5’

to 3’ However, the lagging fragments, known as Okazaki’sfragments, are individually synthesized in the direction 5’ to 3’

by DNA polymerase III RNA polymerases produce the RNAprimers that help DNA polymerases to synthesize the leadingstrand Nevertheless, the small fragments of the lagging strandhave as primers a special RNA that is synthesized by anotherenzyme, the primase Enzyme topoisomerase III does theproofreading of the newly transcribed sequences and elimi-nates those wrongly transcribed, before DNA synthesis maycontinue RNA primers are removed from the newly synthe-sized sequences by ribonuclease H Polymerase I fills the gapsand DNA ligase joins the lagging strands

Cell membrane transport

After DNA replication, each DNA molecule is gated, i.e., separated from the other, and attached to a different

segre-region of the internal face of the membrane The formation of

a septum, or dividing internal wall, separates the cell into

halves, each containing a nucleotide The process of splitting

the cell in two identical daughter cells is known as cytokinesis

See also Bacterial growth and division; Biochemistry; Cell

cycle (eukaryotic), genetic regulation of; Cell cycle and cell

division; Chromosomes, eukaryotic; Chromosomes,

prokary-otic; DNA (Deoxyribonucleic acid); Enzymes; Genetic

regu-lation of eukaryotic cells; Genetic reguregu-lation of prokaryotic

cells; Genotype and phenotype; Molecular biology and

molec-ular genetics

Cell membrane transport

The cell is bound by an outer membrane that, in accord with

the fluid mosaic model, is comprised of a phospholipid lipid

bilayer with proteins—molecules that also act as receptor

sites—interspersed within the phospholipid bilayer Varieties

of channels exist within the membrane There are a number of

internal cellular membranes that partially partition the

inter-cellular matrix, and that ultimately become continuous with

the nuclear membrane

There are three principal mechanisms of outer cellularmembrane transport (i.e., means by which molecules can pass

through the boundary cellular membrane) The transport

mechanisms are passive, or gradient diffusion, facilitated

dif-fusion, and active transport

Diffusion is a process in which the random motions ofmolecules or other particles result in a net movement from a

region of high concentration to a region of lower

concentra-tion A familiar example of diffusion is the dissemination of

floral perfumes from a bouquet to all parts of the motionless

air of a room The rate of flow of the diffusing substance is

proportional to the concentration gradient for a given direction

of diffusion Thus, if the concentration of the diffusing

sub-stance is very high at the source, and is diffusing in a direction

where little or none is found, the diffusion rate will be

maxi-mized Several substances may diffuse more or less

independ-ently and simultaneously within a space or volume of liquid

Because lightweight molecules have higher average speeds

than heavy molecules at the same temperature, they also tend

to diffuse more rapidly Molecules of the same weight move

more rapidly at higher temperatures, increasing the rate of

dif-fusion as the temperature rises

Driven by concentration gradients, diffusion in the cellusually takes place through channels or pores lined by pro-

teins Size and electrical charge may inhibit or prohibit the

passage of certain molecules or electrolytes (e.g., sodium,

potassium, etc.)

Osmosis describes diffusion of water across cell branes Although water is a polar molecule (i.e., has overall par-

mem-tially positive and negative charges separated by its molecular

structure), transmembrane proteins form hydrophilic (water

lov-ing) channels to through which water molecules may move

Facilitated diffusion is the diffusion of a substance notmoving against a concentration gradient (i.e., from a region oflow concentration to high concentration) but which require theassistance of other molecules These are not considered to beenergetic reactions (i.e., energy in the form of use of adenosinetriphosphate molecules (ATP) is not required The facilitation

or assistance—usually in physically turning or orienting amolecule so that it may more easily pass through a mem-brane—may be by other molecules undergoing their own ran-dom motion

Transmembrane proteins establish pores through whichions and some small hydrophilic molecules are able to pass bydiffusion The channels open and close according to the phys-iological needs and state of the cell Because they open andclose transmembrane proteins are termed “gated” proteins.Control of the opening and closing mechanism may be viamechanical, electrical, or other types of membrane changesthat may occur as various molecules bind to cell receptor sites.Active transport is movement of molecules across a cellmembrane or membrane of a cell organelle, from a region oflow concentration to a region of high concentration Sincethese molecules are being moved against a concentration gra-dient, cellular energy is required for active transport Activetransport allows a cell to maintain conditions different fromthe surrounding environment

There are two main types of active transport; movementdirectly across the cell membrane with assistance from trans-port proteins, and endocytosis, the engulfing of materials into

a cell using the processes of pinocytosis, phagocytosis, orreceptor-mediated endocytosis

Transport proteins found within the phospholipidbilayer of the cell membrane can move substances directlyacross the cell membrane, molecule by molecule The sodium-potassium pump, which is found in many cells and helps nervecells to pass their signals in the form of electrical impulses, is

a well-studied example of active transport using transport teins The transport proteins that are an essential part of thesodium-potassium pump maintain a higher concentration ofpotassium ions inside the cells compared to outside, and ahigher concentration of sodium ions outside of cells compared

pro-to inside In order pro-to carry the ions across the cell membraneand against the concentration gradient, the transport proteinshave very specific shapes that only fit or bond well withsodium and potassium ions Because the transport of theseions is against the concentration gradient, it requires a signifi-cant amount of energy

Endocytosis is an infolding and then pinching in of thecell membrane so that materials are engulfed into a vacuole orvesicle within the cell Pinocytosis is the process in whichcells engulf liquids The liquids may or may not contain dis-solved materials Phagocytosis is the process in which thematerials that are taken into the cell are solid particles Withreceptor-mediated endocytosis the substances that are to betransported into the cell first bind to specific sites or receptorproteins on the outside of the cell The substances can then beengulfed into the cell As the materials are being carried intothe cell, the cell membrane pinches in forming a vacuole orother vesicle The materials can then be used inside the cell

Centers for Disease Control • WORLD OF MICROBIOLOGY AND IMMUNOLOGY

Because all types of endocytosis use energy, they are

consid-ered active transport

See also Bacterial growth and division; Biochemistry; Cell

cycle and cell division; Enzymes; Molecular biology and

molecular genetics

Centers for Disease Control

The Centers for Disease Control and Prevention (CDC) is one

of the primary public healthinstitutions in the world CDC is

headquartered in Atlanta, Georgia, with facilities at 9 other

sites in the United States The centers are the focus of the

United States government efforts to develop and implementprevention and control strategies for diseases, including those

of microbiological origin

The CDC is home to 11 national centers that addressvarious aspects of health care and disease prevention.Examples of the centers include the National Center forChronic Disease Prevention and Health promotion, NationalCenter for Infectious Diseases, National Immunization

Program, and the National Center for HIV, STD, and TBPrevention

CDC was originally the acronym for The cable Disease Center This center was a redesignation of anexisting facility known as the Malaria Control in War Areas.The malaria control effort had been mandated to eradicate

Communi-View down the channel of the matrix porin of Escherichia coli.

Chagas disease

malariafrom the southern United States during World War II

The Communicable Disease Center began operations in

Atlanta on July 1, 1946, under the direction of Dr Joseph M

Mountin

Initially, the center was very small and was staffedmainly by engineers and entomologists (scientists who study

insects) But under Mountin’s direction, an expansion program

was begun with the intent of making the center the

predomi-nant United States center of epidemiology By 1950 the center

had opened a disease surveillance unit that remains a

corner-stone of CDC’s operations today Indeed, during the Korean

War, the Epidemiological Intelligence Service was created, to

protect the United States from the immigration of disease

causing microorganisms

Two events in the 1950s brought the CDC to nationalprominence and assured the ongoing funding of the center The

first event was the outbreak of poliomyelitis in children who

had received an inoculation with the recently approved Salk

polio vaccine A Polio Surveillance Unit that was established at

CDC confirmed the cause of the cases to be due to a

contami-nated batch of the vaccine With CDC’s help, the problem was

solved and the national polio vaccination program

recom-menced The other event was a massive outbreak of influenzae

Data collected by CDC helped pave the way for the

develop-ment of influenzavaccines and inoculation programs

In the 1950s and 1960s, CDC became the center forvenereal disease, tuberculosis, and immunization programs

The centers also played a pivotal role in the eradication of

smallpox, through the development of a vaccine and an

inoc-ulation instrument Other accomplishments include the

identi-fication of Legionnaire’s diseaseand toxic shock syndromein

the 1970s and 1980s, hantavirus pulmonary syndrome in

1993, and, beginning in 1981, a lead role in the research and

treatment of Acquired ImmunodeficiencySyndrome

In 1961, CDC took over the task of publishing

Morbidity and Mortality Weekly Report Then as now, the

MMWR is a definitive weekly synopsis of data on deaths and

selected diseases from every state in the United States A

note-worthy publication in MMWR was the first report in a 1981

issue of the disease that would come to be known as Acquired

Immunodeficiency Syndrome

Another advance took place in 1978, with the opening

of a containment facility that could be used to study the most

lethal virusesknown to exist (e.g., Ebola) Only a few such

facilities exist in the world Without such high containment

facilities, hemorrhagic viruses could not be studied, and

devel-opment of vaccines would be impossible

Ultimately, CDC moved far beyond its original mandate

as a communicable disease center To reflect this change, the

name of the organization was changed in 1970 to the Center

for Disease Control In 1981, the name was again changed to

the Centers for Disease Control The subsequent initiation of

programs designed to target chronic diseases, breast and

cer-vical cancers and lifestyle issues (e.g., smoking) extended

CDC’s mandate beyond disease control Thus, in 1992, the

organization became the Centers for Disease Control and

Prevention (the acronym CDC was retained)

Today, CDC is a world renowned center of excellencefor public health research, disease detection, and dissemina-tion of information on a variety of diseases and health issues

See also AIDS, recent advances in research and treatment;

Bacteria and bacterial infection; History of public health;Public health, current issues

C EPHALOSPORINS • see ANTIBIOTICS

Chagas disease

Chagas disease is a human infection that is caused by amicroorganism that establishes a parasitic relationship with ahuman host as part of its life cycle The disease is named forthe Brazilian physician Carlos Chagas, who described in 1909the involvement of the flagellated protozoan known as

Trypanosoma cruzi in a prevalent disease in South America.

The disease is confined to North, South, and CentralAmerica Reflecting this, and the similarity of the disease totrypanosomiasis, a disease that occurs on the African conti-nent, Chagas disease has also been dubbed American try-panosomiasis The disease affects some 16 to 18 million eachyear, mainly in Central and South American Indeed, in theseregions the prevalence of Chagas disease in the population ishigher than that of the Human Immunodeficiency Virusand the

HepatitisB and C viruses Of those who acquire Chagas ease, approximately 50,000 people die each year

dis-The agent of Chagas disease, Trypanosoma cruzi, is a

member of a division, or phylum, called Sarcomastigophora.The protozoan is spread to human via a bug known asReduviid bugs (or “kissing bugs”) These bugs are also known

as triatomines Examples of species include Triatoma tans, Triatoma brasiliensis, Triatoma dimidiata, and Triatoma sordida.

infes-The disease is spread because of the close proximity ofthe triatomine bugs and humans The bugs inhabit houses, par-ticularly more substandard houses where cracks and deterio-rating framework allows access to interior timbers Biting analready infected person or animal infects the bugs themselves.The protozoan lives in the digestive tract of the bug Theinfected bug subsequently infects another person by defecat-ing on them, often while the person is asleep and unaware ofthe bug’s presence The trypanosomes in the feces gain entry

to the bloodstream when feces are accidentally rubbed into thebite, or other orifices such as the mouth or eyes

Chagas disease can also be transmitted in the blood.Acquisition of the disease via a blood transfusion occurs inthousands of people each year

The association between the Reduviid bug and poorquality housing tends to make Chagas disease prevalent inunderdeveloped regions of Central and South America To add

to the burden of these people, some 30% of those who areinfected in childhood develop a chronic form of the disease 10

Chain, Ernst Boris • WORLD OF MICROBIOLOGY AND IMMUNOLOGY

to 20 years later This long-lasting form of Chagas disease

reduces the life span by almost a decade

Chagas disease may be asymptomatic (without toms)—or can produce a variety of symptoms The form of the

symp-disease that strikes soon after infection with Trypanosoma

cruzi tends to persist only for a few months before

disappear-ing Usually, no treatment is necessary for relief from the

infection Symptoms of this type of so-called acute infection

include swelling at the site of the bug bite, tiredness, fever,

enlarged spleen or liver, diarrhea, and vomiting Infants can

experience a swelling of the brain that can be fatal

The chronic form of Chagas disease can produce moresevere symptoms, including an enlarged heart, irregularities in

heart function, and the enlargement and malfunction of the

digestive tract These symptoms are of particular concern in

those people whose immune systemis not functioning properly

Currently, there is no vaccine or other preventativetreatment for Chagas disease Avoidance of habitats where the

Reduviid bug lives is the most prudent precaution

Unfortunately, given the economic circumstances of those

most at risk, this option is not easily attainable Trypanosoma

cruzi can also be transmitted in the blood Therefore,

screen-ing of blood and blood products for the presence of the

proto-zoan is wise Once again, however, the poverty that often

plays a role in the spread of Chagas disease may also be

reflected in less than adequate medical practices, including

blood screening

See also Parasites; Zoonoses

Chain, Ernst Boris

German–born English biochemist

Ernst Chain was instrumental in the creation of penicillin, the

first antibiotic drug Although the Scottish bacteriologist

Alexander Flemingdiscovered the penicillium notatummold

in 1928, it was Chain who, together with Howard Florey,

iso-lated the breakthrough substance that has saved countless

victims of infections For their work, Chain, Florey, and

Fleming were awarded the Nobel Prize in physiology or

medicine in 1945

Chain was born in Berlin to Michael Chain andMargarete Eisner Chain His father was a Russian immigrant

who became a chemical engineer and built a successful

chem-ical plant The death of Michael Chain in 1919, coupled with

the collapse of the post–World War I German economy,

depleted the family’s income so much that Margarete Chain

had to open up her home as a guesthouse

One of Chain’s primary interests during his youth wasmusic, and for a while it seemed that he would embark on a

career as a concert pianist He gave a number of recitals and

for a while served as music critic for a Berlin newspaper A

cousin, whose brother–in–law had been a failed conductor,

gradually convinced Chain that a career in science would be

more rewarding than one in music Although he took lessons

in conducting, Chain graduated from Friedrich–Wilhelm

University in 1930 with a degree in chemistry and physiology

Chain began work at the Charite Hospital in Berlinwhile also conducting research at the Kaiser Wilhelm Institutefor Physical Chemistry and Electrochemistry But the increas-ing pressures of life in Germany, including the growingstrength of the Nazi party, convinced Chain that, as a Jew, hecould not expect a notable professional future in Germany.Therefore, when Hitler came to power in January 1933, Chaindecided to leave Like many others, he mistakenly believedthe Nazis would soon be ousted His mother and sister chosenot to leave, and both died in concentration camps

Chain arrived in England in April 1933, and soonacquired a position at University College Hospital MedicalSchool He stayed there briefly and then went to Cambridge towork under the biochemist Frederick Gowland Hopkins.Chain spent much of his time at Cambridge conductingresearch on enzymes In 1935, Howard Florey became head ofthe Sir William Dunn School of Pathology at Oxford Florey,

an Australian–born pathologist, wanted a top–notch chemist to help him with his research, and asked Hopkins foradvice Without hesitation, Hopkins suggested Chain.Florey was actively engaged in research on the bacteri-olytic substance lysozyme, which had been identified byFleming in his quest to eradicate infection Chain came acrossFleming’s reports on the penicillin mold and was immediatelyintrigued He and Florey both saw great potential in the furtherinvestigation of penicillin With the help of a RockefellerFoundation grant, the two scientists assembled a research teamand set to work on isolating the active ingredient in

bio-Penicillium notatum.

Fleming, who had been unable to identify the terial agent in the mold, had used the mold broth itself in hisexperiments to kill infections Assisted in their research by fel-low scientist Norman Heatley, Chain and Florey began theirwork by growing large quantities of the mold in the Oxfordlaboratory Once there were adequate supplies of the mold,Chain began the tedious process of isolating the “miracle”substance Succeeding after several months in isolating smallamounts of a powder that he obtained by freeze–drying themold broth, Chain was ready for the first practical test Hisexperiments with laboratory mice were successful, and it wasdecided that more of the substance should be produced to try

antibac-on humans To do this, the scientists needed to ferment sive quantities of mold broth; it took 125 gallons of the broth

mas-to make enough penicillin powder for one tablet By 1941,Chain and his colleagues had finally gathered enough peni-cillin to conduct experiments with patients The first two ofeight patients died from complications unrelated to their infec-tions, but the remaining six, who had been on the verge ofdeath, were completely cured

One potential use for penicillin was the treatment ofwounded soldiers, an increasingly significant issue during theSecond World War For penicillin to be widely effective, how-ever, the researchers needed to devise a way to mass–producethe substance Florey and Heatley went to the United States in

1941 to enlist the aid of the government and of pharmaceuticalhouses New ways were found to yield more and stronger peni-cillin from mold broth, and by 1943, the drug went into regu-lar medical use for Allied troops After the war, penicillin was

made available for civilian use The ethics of whether to make

penicillin research universally available posed a particularly

difficult problem for the scientific community during the war

years While some believed that the research should not be

shared with the enemy, others felt that no one should be denied

the benefits of penicillin This added layers of political intrigue

to the scientific pursuits of Chain and his colleagues Even after

the war, Chain experienced firsthand the results of this

dilemma As chairman of the World Health Organizationin the

late 1940s, Chain had gone to Czechoslovakia to supervise the

operation of penicillin plants established there by the United

Nations He remained there until his work was done, even

though the Communist coup occurred shortly after his arrival

When Chain applied for a visa to visit the United States in

1951, his request was denied by the State Department Though

no reason was given, many believed his stay in

Czechoslovakia, however apolitical, was a major factor

After the war, Chain tried to convince his colleaguesthat penicillin and other antibiotic research should be

expanded, and he pushed for more state-of-the-art facilities at

Oxford Little came of his efforts, however, and when the

Italian State Institute of Public Health in Rome offered him the

opportunity to organize a biochemical and microbiological

department along with a pilot plant, Chain decided to leave

Oxford

Under Chain’s direction, the facilities at the StateInstitute became known internationally as a center for

advanced research While in Rome, Chain worked to develop

new strains of penicillin and to find more efficient ways to

produce the drug Work done by a number of scientists, with

Chain’s guidance, yielded isolation of the basic penicillin

mol-ecule in 1958, and hundreds of new penicillin strains were

soon synthesized

In 1963, Chain was persuaded to return to England TheUniversity of London had just established the Wolfson

Laboratories at the Imperial College of Science and

Technology, and Chain was asked to direct them Through his

hard work the Wolfson Laboratories earned a reputation as a

first–rate research center

In 1948, Chain had married Anne Beloff, a fellow chemist, and in the following years she assisted him with his

bio-research She had received her Ph.D from Oxford and had

worked at Harvard in the 1940s The couple had three children

Chain retired from Imperial College in 1973, but tinued to lecture He cautioned against allowing the then-new

con-field of molecular biologyto downplay the importance of

bio-chemistryto medical research He still played the piano, for

which he had always found time even during his busiest

research years Over the years, Chain also became

increas-ingly active in Jewish affairs He served on the Board of

Governors of the Weizmann Institute in Israel, and was an

out-spoken supporter of the importance of providing Jewish

edu-cation for young Jewish children in England and abroad—all

three of his children received part of their education in Israel

In addition to the Nobel Prize, Chain received theBerzelius Medal in 1946, and was made a commander of the

Legion d’Honneur in 1947 In 1954, he was awarded the Paul

Ehrlich Centenary Prize Chain was knighted by QueenElizabeth II in 1969 Chain died of heart failure at age 73

See also Antibiotic resistance, tests for; Bacteria and

responses to bacterial infection; Chronic bacterial disease;Staphylococci and staphylococcal infections

Chaperones

The last two decades of the twentieth century saw the discovery

of the heat-shock or cell-stress response, changes in the sion of certain proteins, and the unraveling of the function ofproteins that mediate this essential cell-survival strategy Theproteins made in response to the stresses are called heat-shockproteins, stress proteins, or molecular chaperones A large num-ber of chaperones have been identified in bacteria (includingarchaebacteria), yeast, and eukaryotic cells Fifteen differentgroups of proteins are now classified as chaperones Theirexpression is often increased by cellular stress Indeed, manywere identified as heat-shock proteins, produced when cellswere subjected to elevated temperatures Chaperones likelyfunction to stabilize proteins under less than ideal conditions.The term chaperone was coined only in 1978, but theexistence of chaperones is ancient, as evidenced by the con-servation of the peptide sequences in the chaperones fromprokaryotic and eukaryotic organisms, including humans.Chaperones function 1) to stabilize folded proteins, 2)unfold them for translocation across membranes or for degra-dation, or 3) to assist in the proper folding of the proteins dur-ing assembly These functions are vital Accumulation ofunfolded proteins due to improper functioning of chaperonescan be lethal for cells Prionsserve as an example Prions are

exan infectious agent composed solely of protein They are ent in both healthy and diseased cells The difference is that indiseased cells the folding of the protein is different.Accumulation of the misfolded proteins in brain tissue killsnerve cells The result for the affected individual can bedementia and death, as in the conditions of kuru, Creutzfeld-Jakob disease and “mad cow” disease (bovine spongiformencephalopthy)

pres-Chaperones share several common features They act with unfolded or partially folded protein subunits, nascentchains emerging from the ribosome, or extended chains beingtranslocated across subcellular membranes They do not, how-ever, form part of the final folded protein molecule.Chaperones often facilitate the coupling of cellular energysources (adenosine triphosphate; ATP) to the folding process.Finally, chaperones are essential for viability

Chaperones differ in that some are non-specific, acting with a wide variety of polypeptide chains, while othersare restricted to specific targets Another difference concernstheir shape; some are donut-like, with the central zone as thedirect interaction region, while others are block-like, tunnel-like, or consist of paired subunits

inter-The reason for chaperone’s importance lies with theenvironment within cells Cells have a watery environment,yet many of the amino acids in a protein are hydrophobic

Chase, Martha Cowles • WORLD OF MICROBIOLOGY AND IMMUNOLOGY

(water hating) These are hidden in the interior of a correctly

folded protein, exposing the hydrophilic (water loving) amino

acids to the watery interior solution of the cell If folded in

such a correct manner, tensions are minimized and the

three-dimensional structure of the protein is stable Chaperons

func-tion to aid the folding process, ensuring protein stability and

proper function

Protein folding occurs by trial and error If the proteinfolds the wrong way, it is captured by a chaperone, and

another attempt at folding can occur Even correctly folded

proteins are subject to external stress that can disrupt structure

The chaperones, which are produced in greater amounts when

a cell is exposed to higher temperatures, function to stabilize

the unraveling proteins until the environmental crisis passes

Non-biological molecules can also participate as erones In this category, protein folding can be increased by

chap-the addition of agents such as glycerol, guanidium chloride,

urea, and sodium chloride Folding is likely due to an

electro-static interaction between exposed charged groups on the

unfolded protein and the anions

Increasing attention is being paid to the potential roles ofchaperones in human diseases, including infection and idio-

pathic conditions such as arthritis and atherosclerosis One

sub-group of chaperones, the chaperonins, has received the most

attention in this regard, because, in addition to facilitating

pro-tein folding, they also act as cell-to-cell signaling molecules

See also Proteins and enzymes

Chase, Martha Cowles

American geneticist

Martha Cowles Chase is remembered for a landmark

experi-ment in genetics carried out with American geneticist Alfred

Day Hershey (1908–1997) Their experiment indicated that,

contrary to prevailing opinion in 1952, DNAwas genetic

mate-rial A year later, James D Watson and British biophysicist

Francis Crick proposed their double helical model for the

three-dimensional structure of structure of DNA Hershey was

honored as one of the founders of molecular biology, and

shared the 1969 Nobel Prize in medicine or physiology with

Salvador Luria and Max Delbrück

Martha Chase was born in Cleveland, Ohio She earned abachelor’s degree from the College of Wooster in 1950 and her

doctoral degree from the University of Southern California in

1964 Having married and changed her name to Martha C

Epstein (Martha Cowles Chase Epstein), she later returned to

Cleveland Heights, Ohio, where she lived with her father,

Samuel W Chase After graduating from college, Chase worked

as an assistant to Alfred Hershey at the Carnegie Institution of

Washington in Cold Spring Harbor, New York This was a

crit-ical period in the history of modern genetics and the beginning

of an entirely new phase of research that established the science

of molecular biology Including the name of an assistant or

tech-nician on a publication, especially one that was certain to

become a landmark in the history of molecular biology, was

unusual during the 1960s Thus, it is remarkable that Martha

Chase’s name is inextricably linked to all accounts of the path

to the demonstration that DNA is the genetic material

During the 1940s, most chemists, physicists, and cists thought that the genetic material must be a protein, butresearch on the bacteriathat cause pneumoniasuggested thenucleic acids played a fundamental role in inheritance Thefirst well-known series of experiments to challenge theassumption that genes must be proteins or nucleoproteins wascarried out by Oswald T Avery(1877–1955) and his co-work-ers Colin Macleod, and Maclyn McCartyin 1944 Avery’s workwas a refinement of observations previously reported in 1928

geneti-by Fred Griffith (1877–1941), a British bacteriologist Averyidentified the transforming principle of bacterial types asDNA and noted that further studies of the chemistry of DNAwere required in order to explain its biological activity.Most geneticists were skeptical about the possibilitythat DNA could serve as the genetic material until the results

of the Hershey-Chase experiments of 1952 were reported.Their experiments indicated that bacteriophages (virusesthatattack bacteria) might act like tiny syringes containing thegenetic material and the empty virus containers might remainoutside the bacterial cell after the genetic material of the virushad been injected To test this possibility, Hershey and Chaseused radioactive sulfur to label bacteriophage proteins andradioactive phosphate to label their DNA After allowingviruses to attack the bacterial cells, the bacterial cultures werespun in a blender and centrifuged in order to separate intactbacteria from smaller particles

Hershey and Chase found that most of the phage DNA remained with the bacterial cells while their pro-tein coats were released into the medium They concluded thatthe protein played a role in adsorption to the bacteria andhelped inject the viral DNA into the bacterial cell Thus, it wasthe DNA that was involved in the growth and multiplication ofbacteriophage within the infected bacterial cell Friends ofAlfred Hershey recalled that when he was asked for his con-cept of the greatest scientific happiness, he said it would be tohave an experiment that works The Hershey-Chase experi-ments became a proverbial example of what his friends andcolleagues called “Hershey Heaven.”

bacterio-See also Bacteriophage and bacteriophage typing; DNA

(Deoxyribonucleic acid); Molecular biology and moleculargenetics; Molecular biology, central dogma of; Viral genetics

chemical-an outcome of inherited traits Chemicals capable of inducinggenetic mutation (i.e., chemical mutagenes or genotoxic com-pounds) are present in both natural and man-made environ-ments and products

Chemoautotrophic and chemolithotrophic bacteria

Many plants, including edible ones, produce discreetamounts of some toxic compound that plays a role in plant

protection against some natural predator Some of these

natu-ral compounds may also be genotoxic for humans and

ani-mals, when that plant is consumed frequently and in great

amounts For instance, most edible mushrooms contain a

fam-ily of chemical mutagenes known as hydrazines; but once

mushrooms are cooked, most hydrazines evaporate or are

degraded into less toxic compounds

Among the most aggressive man-made chemical genes are:

muta-• asbestos

• DDT

• insecticides and herbicides containing arsenic

• industrial products containing benzene

cities and industrial districts For instance, insecticide and

her-bicide sprayers on farms, tanners, and oil refinery workers are

frequently exposed to arsenic and may suffer mutations that

lead to lung or skin cancers Insulation and demolition

work-ers are prone to contaminationwith asbestos and may

eventu-ally develop lung cancer Painters, dye users, furniture

finishers, and rubber workers are often exposed to benzene,

which can induce mutations in stem cells that generate white

blood cells, thus causing myelogenous leukemia People

working in the manufacture of wood products, paper, textiles

and metallurgy, as well as hospital and laboratory workers, are

frequently in contact with formaldehyde and can thus suffer

mutations leading to nose and nasopharynx tumors Cigarette

and cigar smoke contains a class of chemical mutagenes,

known as PAH (polycyclic aromatic hydrocarbons), that leads

to mutation in lung cells PAH is also present in gas and diesel

combustion fumes

Except for the cases of accidental high exposure andcontamination, most chemical mutagenes or their metabolites

(i.e., cell-transformed by-products) have a progressive and

gradual accumulation in DNA, throughout years of

exposi-tion Some individuals are more susceptible to the effects of

cumulative contamination than others Such individual

degrees of susceptibility are due to discreet genetic

varia-tions, known as polymorphism, meaning several forms or

versions of a given group of genes Depending on the

poly-morphic version of Cytochrome P450 genes, an individual

may metabolize some mutagenes faster than others

Polymorphism in another group of genes, NAT

(N-acetyl-transferase), is also implied in different individual

suscepti-bilities to chemical exposure and mutagenesis

See also Immunogenetics; Mutants, enhanced tolerance or

sensitivity to temperature and pH ranges; Mutations and

muta-genesis

CHEMOLITHOTROPHIC BACTERIA

Chemoautotrophic and chemolithotrophic bacteria

Autotrophic bacteriaobtain the carbon that they need to tain survival and growth from carbon dioxide (CO2) Toprocess this carbon source, the bacteria require energy.Chemoautotrophic bacteria and chemolithotrophic bacteriaobtain their energy from the oxidation of inorganic (non-car-bon) compounds That is, they derive their energy from theenergy already stored in chemical compounds By oxidizingthe compounds, the energy stored in chemical bonds can beutilized in cellular processes Examples of inorganic com-pounds that are used by these types of bacteria are sulfur,ammonium ion (NH4+), and ferrous iron (Fe2+)

sus-The designation autotroph means “self nourishing.”Indeed, both chemoautotrophs and chemolithotrophs are able

to grow on medium that is free of carbon The designationlithotrophic means “rock eating,” further attesting to the abil-ity of these bacteria to grow in seemingly inhospitable envi-ronments

Most bacteria are chemotrophic If the energy sourceconsists of large chemicals that are complex in structure, as isthe case when the chemicals are derived from once-livingorganisms, then it is the chemoautotrophic bacteria that utilizethe source If the molecules are small, as with the elementslisted above, they can be utilized by chemolithotrophs.Only bacteria are chemolithotrophs Chemoautotrophsinclude bacteria, fungi, animals, and protozoa

There are several common groups of chemoautotrophicbacteria The first group is the colorless sulfur bacteria Thesebacteria are distinct from the sulfur bacteria that utilize sun-light The latter contain the compound chlorophyll, and soappear colored Colorless sulfur bacteria oxidize hydrogensulfide (H2S) by accepting an electron from the compound.The acceptance of an electron by an oxygen atom createswater and sulfur The energy from this reaction is then used toreduce carbon dioxide to create carbohydrates An example of

a colorless sulfur bacteria is the genus Thiothrix.

Another type of chemoautotroph is the “iron” bacteria.These bacteria are most commonly encountered as the rustycoloured and slimy layer that builds up on the inside of toilettanks In a series of chemical reactions that is similar to those

of the sulfur bacteria, iron bacteria oxidize iron compoundsand use the energy gained from this reaction to drive the for-mation of carbohydrates Examples of iron bacteria are

Thiobacillus ferrooxidans and Thiobacillus thiooxidans.

These bacteria are common in the runoff from coal mines Thewater is very acidic and contains ferrous iron Chemoauto-trophs thrive in such an environment

A third type of chemoautotrophic bacteria includes thenitrifying bacteria These chemoautotrophs oxidize ammonia(NH3) to nitrate (NO3-) Plants can use the nitrate as a nutrientsource These nitrifying bacteria are important in the operation

of the global nitrogen cycle Examples of chemoautotrophicnitrifying bacteria include Nitrosomonas and Nitrobacter.The evolutionof bacteria to exist as chemoautotrophs orchemolithotrophs has allowed them to occupy niches that

Chemotherapy • WORLD OF MICROBIOLOGY AND IMMUNOLOGY

would otherwise be devoid of bacterial life For example, in

recent years scientists have studied a cave near Lovell,

Wyoming The groundwater running through the cave

con-tains a strong sulfuric acid Moreover, there is no sunlight The

only source of life for the thriving bacterial populations that

adhere to the rocks are the rocks and the chemistry of the

groundwater

The energy yield from the use of inorganic compounds

is not nearly as great as the energy that can be obtained by other

types of bacteria But, chemoautotrophs and chemolithotrophs

do not usually face competition from other microorganisms, so

the energy they are able to obtain is sufficient to sustain their

existence Indeed, the inorganic processes associated with

chemoautotrophs and chemolithotrophs may make these

bacte-ria one of the most important sources of weathering and

ero-sion of rocks on Earth

The ability of chemoautotrophic and chemolithotrophicbacteria to thrive through the energy gained by inorganic

processes is the basis for the metabolic activities of the so-called

extremophiles These are bacteria that live in extremes of pH,

temperature of pressure, as three examples Moreover, it has

been suggested that the metabolic capabilities of extremophiles

could be duplicated on extraterrestrial planetary bodies

See also Metabolism

LABORATORY TECHNIQUES IN MICROBIOLOGY

C HEMOTAXIS • see BACTERIAL MOVEMENT

Chemotherapy

Chemotherapy is the treatment of a disease or condition with

chemicals that have a specific effect on its cause, such as a

microorganism or cancer cell The first modern therapeutic

chemical was derived from a synthetic dye The sulfonamide

drugs developed in the 1930s, penicillinand other antibiotics

of the 1940s, hormones in the 1950s, and more recent drugs

that interfere with cancer cell metabolism and reproduction

have all been part of the chemotherapeutic arsenal

The first drug to treat widespread bacteriawas oped in the mid-1930s by the German physician-chemist

devel-Gerhard Domagk In 1932, he discovered that a dye named

prontosil killed streptococcus bacteria, and it was quickly used

medically on both streptococcus and staphylococcus One of

the first patients cured with it was Domagk’s own daughter In

1936, the Swiss biochemist Daniele Bovet, working at the

Pasteur Institute in Paris, showed that only a part of prontosil

was active, a sulfonamide radical long known to chemists

Because it was much less expensive to produce, sulfonamide

soon became the basis for several widely used “sulfa drugs”

that revolutionized the treatment of formerly fatal diseases

These included pneumonia, meningitis, and puerperal

(“childbed”) fever For his work, Domagk received the 1939Nobel Prize in physiology or medicine Though largelyreplaced by antibiotics, sulfa drugsare still commonly usedagainst urinary tract infections, Hanson disease (leprosy),

malaria, and for burn treatment

At the same time, the next breakthrough in apy, penicillin, was in the wings In 1928, the British bacteri-ologist Alexander Fleming noticed that a mold on anuncovered laboratory dish of staphylococcus destroyed the

chemother-bacteria He identified the mold as Penicillium notatum, which

was related to ordinary bread mold Fleming named the mold’sactive substance penicillin, but was unable to isolate it

In 1939, the American microbiologist René Jules Dubos

(1901–1982) isolated from a soil microorganism an rial substance that he named tyrothricin This led to wide inter-est in penicillin, which was isolated in 1941 by two biochemists

antibacte-at Oxford University, Howard Floreyand Ernst Chain.The term antibiotic was coined by American microbi-ologist Selman Abraham Waksman, who discovered the firstantibiotic that was effective on gram-negative bacteria.Isolating it from a Streptomyces fungus that he had studiedfor decades, Waksman named his antibiotic streptomycin.Though streptomycin occasionally resulted in unwanted sideeffects, it paved the way for the discovery of other antibiotics.The first of the tetracyclines was discovered in 1948 by theAmerican botanist Benjamin Minge Duggar Working with

Streptomyces aureofaciens at the Lederle division of the

American Cyanamid Co., Duggar discovered cline (Aureomycin)

chlortetracy-The first effective chemotherapeutic agent against

viruses was acyclovir, produced in the early 1950s by theAmerican biochemists George Hitchings and Gertrude Belle Elionfor the treatment of herpes Today’s antiviral drugsarebeing used to inhibit the reproductive cycle of both DNAand

RNA viruses For example, two drugs are used against the

influenzaA virus, Amantadine and Rimantadine, and the AIDS

treatment drug AZT inhibits the reproduction of the human immunodeficiency virus(HIV)

Cancer treatment scientists began trying various cal compounds for use as cancer treatments as early as themid-nineteenth century But the first effective treatments werethe sex hormones, first used in 1945, estrogens for prostatecancer and both estrogens and androgens to treat breast cancer

chemi-In 1946, the American scientist Cornelius Rhoads developedthe first drug especially for cancer treatment It was an alky-lating compound, derived from the chemical warfare agentnitrogen mustard, which binds with chemical groups in thecell’s DNA, keeping it from reproducing Alkylating com-pounds are still important in cancer treatment

In the next twenty years, scientists developed a series ofuseful antineoplastic (anti-cancer) drugs, and, in 1954, theforerunner of the National Cancer Institute was established inBethesda, MD Leading the research efforts were the so-called

“4-H Club” of cancer chemotherapy: the Americans CharlesHuggins (1901–1997), who worked with hormones; GeorgeHitchings (1905–1998), purines and pyrimidines to interferewith cell metabolism; Charles Heidelberger, fluorinated com-pounds; and British scientist Alexander Haddow (1907–1976),

who worked with various substances The first widely used

drug was 6-Mercaptopurine, synthesized by Elion and

Hitchings in 1952

Chemotherapy is used alone, in combination, and alongwith radiation and/or surgery, with varying success rates,

depending on the type of cancer and whether it is localized or

has spread to other parts of the body They are also used after

treatment to keep the cancer from recurring (adjuvant

ther-apy) Since many of the drugs have severe side effects, their

value must always be weighed against the serious short-and

long-term effects, particularly in children, whose bodies are

still growing and developing

In addition to the male and female sex hormones gen, estrogen, and progestins, scientists also use the hormone

andro-somatostatin, which inhibits production of growth hormone

and growth factors They also use substances that inhibit the

action of the body’s own hormones An example is Tamoxifen,

used against breast cancer Normally the body’s own estrogen

causes growth of breast tissues, including the cancer The drug

binds to cell receptors instead, causing reduction of tissue and

cancer cell size

Forms of the B-vitamin folic acid were found to be ful in disrupting cancer cell metabolism by the American sci-

use-entist Sidney Farber (1903–1973) in 1948 Today they are

used on leukemia, breast cancer, and other cancers

Plant alkaloids have long been used as medicines, such

as colchicine from the autumn crocus Cancer therapy drugs

include vincristine and vinblastine, derived from the pink

peri-winkle by American Irving S Johnson (1925– ) They prevent

mitosis (division) in cancer cells VP-16 and VM-16 are

derived from the roots and rhizomes of the may apple or

man-drake plant, and are used to treat various cancers Taxol, which

is derived from the bark of several species of yew trees, was

discovered in 1978, and is used for treatment of ovarian and

breast cancer

Another class of naturally occurring substances areanthracyclines, which scientists consider to be extremely use-

ful against breast, lung, thyroid, stomach, and other cancers

Certain antibiotics are also effective against cancer cells

by binding to DNA and inhibiting RNA and protein synthesis

Actinomycin D, derived from Streptomyces, was discovered

by Selman Waksman and first used in 1965 by American

researcher Seymour Farber It is now used against cancer of

female reproductive organs, brain tumors, and other cancers

A form of the metal platinum called cisplatin stops cer cells’ division and disrupts their growth pattern Newer

can-treatments that are biological or based on proteins or genetic

material and can target specific cells are also being developed

Monoclonal antibodies are genetically engineered copies of

proteins used by the immune system to fight disease

Rituximab was the first moncoclonal antibodyapproved for

use in cancer, and more are under development Interferons

are proteins released by cells when invaded by a virus

Interferons serve to alert the body’s immune system of an

impending attack, thus causing the production of other

pro-teins that fight off disease Interferons are being studied for

treating a number of cancers, including a form of skin cancer

called multiple myeloma A third group of drugs are called

anti-sense drugs, which affect specific genes within cells.Made of genetic material that binds with and neutralizes mes-senger-RNA, anti-sense drugs halt the production of proteinswithin the cancer cell

Genetically engineered cancer vaccines are also beingtested against several virus-related cancers, including liver,cervix, nose and throat, kidney, lung, and prostate cancers.The primary goal of genetically engineered vaccines is to trig-ger the body’s immune system to produce more cells that willreact to and kill cancer cells One approach involves isolatingwhite blood cells that will kill cancer and then to find certainantigens, or proteins, that can be taken from these cells andinjected into the patient to spur on the immune system A “vac-cine genegun” has also been developed to inject DNA directlyinto the tumor cell An RNA cancer vaccine is also beingtested Unlike most vaccines, which have been primarily tai-lored for specific patients and cancers, the RNA cancer vac-cine is designed to treat a broad number of cancers in manypatients

As research into cancer treatment continues, new cer-fighting drugs will continue to become part of the medicalarmamentarium Many of these drugs will come from the bur-geoning biotechnology industry and promise to have fewerside effects than traditional chemotherapy and radiation

can-See also Antibiotic resistance, tests for; Antiviral drugs;

Bacteria and bacterial infection; Blood borne infections; Cellcycle and cell division; Germ theory of disease; History ofmicrobiology; History of public health; Immunization

C HICKEN POX • see ANTIBIOTICS

Chitin

Chitin is a polymer, a repeating arrangement of a chemicalstructure Chitin is found in the supporting structures of manyorganisms Of relevance to microbiology, chitin is present infungal species such as mushrooms, where it can comprisefrom 5% to 20% of the weight of the organism

The backbone of chitin is a six-member carbon ring thathas side groups attached to some of the carbon atoms Thisstructure is very similar to that of cellulose One of the sidegroups of chitin is known as acetamide, whereas cellulose hashydroxy (OH) side groups

Chitin is a noteworthy biological feature because it isconstructed solely from materials that are naturally available

In contrast, most polymers are man-made and are comprised

of constituents that must be artificially manufactured.The purpose of chitin is to provide support for theorganism The degree of support depends on the amount andthe thickness of chitin that is present In fungisuch as mush-rooms, chitin confers stability and rigidity, yet allows someflexibility This allows the mushrooms to stand and still beflexible enough to sway without snapping

Chlamydial pneumonia • WORLD OF MICROBIOLOGY AND IMMUNOLOGY

The role of chitin as a support structure is analogous tothe peptidoglycansupportive layer that is a feature of Gram-

positive and Gram-negative bacteria The think peptidoglycan

layer in Gram-positive bacteria provides a rigid and robust

sup-port The peptidoglycan layer in Gram-negative bacteria that is

only one molecule thick does not provide the same degree of

structural support Other mechanical elements of the

Gram-negative cell wall are necessary to shore up the structure

In the ocean, where many creatures contain chitin,

sea-dwelling bacteria called Vibrio furnisii have evolved a sensory

system that detects discarded chitin The bacteria are able to

break down the polymer and use the sugar molecules as

meta-bolic fuel

See also Fungi

Chlamydial pneumonia

Chlamydial pneumoniais a pneumonia cause by one of

sev-eral forms of Chlamydial bacteria The three major forms of

Chlamydia responsible for pneumonia are Chlamydia

pneu-moniae, Chlamydia psittaci, and Chlamydia trachomatis.

In reaction to infection, infected lung tissue maybecome obstructed with secretions As part of a generalized

swelling or inflammationof the lungs, the fluid or pus

secre-tions block the normal vascular exchanges that take place in

the alveolar air sacs Blockage of the alveoli results in a

decreased oxygenation of the blood and deprivation of oxygen

to tissues

Chlamydia pneumoniae (in older literature known as

“Taiwan acute respiratory agent”) usually produces a

condi-tion known as “walking pneumonia,” a milder form of

pneu-monia that may only result in a fever and persistent cough

Although the symptoms are usually mild, they can be

debili-tating and dangerous to at risk groups that include the elderly,

young children, or to individuals already weakened by another

illness Chlamydia pneumoniae spreads easily and the high

transmission rate means that many individuals within a

popu-lation—including at risk individuals can be rapidly exposed

Species of chlamydiae can be directly detected ing cultivation in embryonated egg cultures and immunofluo-

follow-rescence staining or via polymerase chain reaction (PCR)

Chlamydiae can also be detected via specific serologic tests

Chlamydia psittaci is an avian bacteria that is

transmit-ted by human contact with infectransmit-ted birds, feathers from

infected birds, or droppings from infected birds The specific

pneumonia (psittacosis) may be severe and last for several

weeks The pneumonia is generally more dangerous than the

form caused by Chlamydia pneumoniae.

Chlamydia trachomatis is the underlying bacterium

responsible for one of several types of sexually transmitted

dis-eases(STD) Most frequently Chlamydia trachomatis results

in an inflammation of the urethra (nongonococcal urethritis)

and pelvic inflammatory disease Active Chlamydia

trachoma-tis infections are especially dangerous during pregnancy

because the newborn may come in contact with the bacteria in

the vaginal canal and aspirate the bacteria into its lung tissue

from coating left on the mouth and nose Although many borns develop only mild pneumonia, because the lungs of anewborn are fragile, especially in pre-term babies, any infec-tion of lung tissue is serious and can be life-threatening.Specific antibioticsare used to fight chlamydial pneu-monias Erythromycin and erythromycin derivatives are used

new-to combat Chlamydia pneumoniae and Chlamydia tis Tetracycline is usually effective against Chlamydia psittaci.

trachoma-See also Bacteria and bacterial infection; Transmission of

pathogens

Chlorination

Chlorination refers to a chemical process that is used primarily

to disinfect drinking water and spills of microorganisms Theactive agent in chlorination is the element chlorine, or a deriv-ative of chlorine (e.g., chlorine dioxide) Chlorination is aswift and economical means of destroying many, but not all,microorganisms that are a health-threat in fluid such as drink-ing water

Chlorine is widely popular for this application because

of its ability to kill bacteriaand other disease-causing isms at relatively low concentrations and with little risk tohumans The killing effect occurs in seconds Much of thekilling effect in bacteria is due to the binding of chlorine toreactive groups within the membrane(s) of the bacteria Thisbinding destabilizes the membrane, leading to the explosivedeath of the bacterium As well, chlorine inhibits various bio-chemical reactions in the bacterium In contrast to the rapidaction of chlorine, other water disinfectionmethods, such asthe use of ozone or ultraviolet light, require minutes of expo-sure to a microorganism to kill the organism

organ-In many water treatment facilities, chlorine gas ispumped directly into water until it reaches a concentration that

is determined to kill microorganisms, while at the same timenot imparting a foul taste or odor to the water The exact con-centration depends on the original purity of the water supply.For example, surface waters contain more organic material thatacts to absorb the added chlorine Thus, more chlorine needs to

be added to this water than to water emerging from deep ground For a particular treatment facility, the amount of chlo-rine that is effective is determined by monitoring the water forthe amount of chlorine remaining in solution and for so-called

under-indictor microorganisms (e.g., Escherichia coli).

Alternatively, chlorine can be added to water in the form

of a solid compound (e.g., calcium or sodium hypochlorite).Both of these compounds react with water, releasing free chlo-rine Both methods of chlorination are so inexpensive thatnearly every public water purification system in the world hasadopted one or the other as its primary means of destroyingdisease-causing organisms