WHAT IS A GENOME?

A Basic Introduction to the Science Underlying NCBI Resources

WHAT IS A GENOME?

Life is specified by genomes. Every organism, including humans, has a genome that contains all of the biological information needed to build and maintain a living example of that organism. The biological information contained in a genome is encoded in itsdeoxyribonucleic acid (DNA) and is divided into discrete units called genes. Genes code for proteins that attach to the genome at the appropriate positions and switch on a series of reactions called gene expression.

In 1909, Danish botanist Wilhelm Johanssen coined the word genefor the hereditary unit found on a chromosome. Nearly 50 years earlier, Gregor Mendel had characterized hereditary units asfactors— observable differences that were passed from parent to offspring. Today we know that a single gene consists of a unique sequence of DNA that provides the complete instructions to make a functional product, called a protein. Genes instruct each cell type— such as skin, brain, and liver—to make discrete sets of proteins at just the right times, and it is through this specificity that unique organisms arise.

The Physical Structure of the Human Genome

Nuclear DNA Inside each of our cells lies a nucleus, a membrane-bounded region that provides a sanctuary for genetic information. The nucleus contains long strands of DNA that encode this genetic information. A DNA chain is made up of four chemical bases: adenine (A) andguanine (G), which are called purines, and cytosine (C) andthymine (T), referred to as pyrimidines. Each base has a slightly different composition, or combination of oxygen, carbon, nitrogen, and hydrogen. In a DNA chain, every base is attached to a sugar molecule (deoxyribose) and a phosphate molecule, resulting in a nucleic acid or nucleotide. Individual nucleotides are linked through the phosphate group, and it is the precise order, or sequence, of nucleotides that determines the product made from that gene.

Figure 1. The four DNA bases. Each DNA base is made up of the sugar 2'-deoxyribose linked to a phosphate group and one of the four bases depicted above: adenine (top left), cytosine (top right), guanine (bottom left), and thymine (bottom right).

A DNA chain, also called a strand, has a sense of direction, in which one end is chemically different than the other. The so-called 5' end terminates in a 5' phosphate group (-PO4); the 3' end terminates in a 3' hydroxyl group (-OH). This is important because DNA strands are always synthesized in the 5' to 3' direction.

The DNA that constitutes a gene is a double-stranded molecule consisting of two chains running in opposite directions. The chemical nature of the bases in double-stranded DNA creates a slight twisting force that gives DNA its characteristic gently coiled structure, known as the double helix. The two strands are connected to each other by chemical pairing of each base on one strand to a specific partner on the other strand. Adenine (A) pairs with thymine (T), and guanine (G) pairs with cytosine (C). Thus, A-T and G-C base pairs are said to be complementary. This complementary base pairing is what makes DNA a suitable molecule for carrying our genetic information—one strand of DNA can act as a templateto direct the synthesis of a complementary strand. In this way, the information in a DNA sequence is readily copied and passed on to the next generation of cells.

Organelle DNA Not all genetic information is found in nuclear DNA. Both plants and animals have an organelle—a "little organ" within the cell— called the mitochondrion. Each mitochondrion has its own set of genes. Plants also have a second organelle, the chloroplast, which also has its own DNA. Cells often have multiple mitochondria, particularly cells requiring lots of energy, such as active muscle cells. This is because mitochondria are responsible for converting the energy stored in macromolecules into a form usable by the cell, namely, theadenosine triphosphate (ATP) molecule. Thus, they are often referred to as the power generators of the cell. Unlike nuclear DNA (the DNA found within the nucleus of a cell), half of which comes from our mother and half from our father, mitochondrial DNA is only inherited from our mother. This is because mitochondria are only found in the female gametes or "eggs" of sexually reproducing animals, not in the male gamete, or sperm. Mitochondrial DNA also does not recombine; there is no shuffling of genes from one generation to the other, as there is with nuclear genes.

Large numbers of mitochondria are found in the tail of sperm, providing them with an engine that generates the energy needed for swimming toward the egg. However, when the sperm enters the egg during fertilization, the tail falls off, taking away the father's mitochondria.

Why Is There a Separate Mitochondrial Genome? The energy-conversion process that takes place in the mitochondria takes place aerobically, in the presence of oxygen. Other energy conversion processes in the cell take place anaerobically, or without oxygen. The independent aerobic function of these organelles is thought to have evolved from bacteria that lived inside of other simple organisms in a mutually beneficial, or symbiotic, relationship, providing them with aerobic capacity. Through the process of evolution, these tiny organisms became incorporated into the cell, and their genetic systems and cellular functions became integrated to form a single functioning cellular unit. Because mitochondria have their own DNA, RNA, and ribosomes, this scenario is quite possible. This theory is also supported by the existence of a eukaryotic organism, called the amoeba, which lacks mitochondria. Therefore, amoeba must always have a symbiotic relationship with an aerobic bacterium.

Why Study Mitochondria? There are many diseases caused by mutations in mitochondrial DNA (mtDNA). Because the mitochondria produce energy in cells, symptoms of mitochondrial diseases often involve degeneration or functional failure of tissue. For example, mtDNA mutations have been identified in some forms of diabetes, deafness, and certain inherited heart diseases. In addition, mutations in mtDNA are able to accumulate throughout an individual's lifetime. This is different from mutations in nuclear DNA, which has sophisticated repair mechanisms to limit the accumulation of mutations. Mitochondrial DNA mutations can also concentrate in the mitochondria of specific tissues. A variety of deadly diseases are attributable to a large number of accumulated mutations in mitochondria. There is even a theory, the Mitochondrial Theory of Aging, that suggests that accumulation of mutations in mitochondria contributes to, or drives, the aging process. These defects are associated with Parkinson's and Alzheimer's disease, although it is not known whether the defects actually cause or are a direct result of the diseases. However, evidence suggests that the mutations contribute to the progression of both diseases. In addition to the critical cellular energy-related functions, mitochondrial genes are useful to evolutionary biologists because of their maternal inheritance and high rate of mutation. By studying patterns of mutations, scientists are able to reconstruct patterns of migration and evolution within and between species. For example, mtDNA analysis has been used to trace the migration of people from Asia across the Bering Strait to North and South America. It has also been used to identify an ancient maternal lineage from which modern man evolved.

Ribonucleic Acids In addition to mRNA, DNA codes for other forms of RNA, including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), and small nuclear RNAs (snRNAs). rRNAs and tRNAs participate in protein assembly whereas snRNAs aid in a process called splicing —the process of editing of mRNA before it can be used as a template for protein synthesis. Just like DNA, ribonucleic acid (RNA) is a chain, or polymer, of nucleotides with the same 5' to 3' direction of its strands. However, the ribose sugar component of RNA is slightly different chemically than that of DNA. RNA has a 2' oxygen atom that is not present in DNA. Other fundamental structural differences exist. For example, uracil takes the place of the thymine nucleotide found in DNA, and RNA is, for the most part, a single-stranded molecule. DNA directs the synthesis of a variety of RNA molecules, each with a unique role in cellular function. For example, all genes that code for proteins are first made into an RNA strand in the nucleus called a messenger RNA (mRNA). The mRNA carries the information encoded in DNA out of the nucleus to the protein assembly machinery, called theribosome, in the cytoplasm. The ribosome complex uses mRNA as a template to synthesize the exact protein coded for by the gene.

Proteins "DNA makes RNA, RNA makes protein, and proteins make us." Francis Crick Although DNA is the carrier of genetic information in a cell, proteins do the bulk of the work. Proteins are long chains containing as many as 20 different kinds of amino acids. Each cell contains thousands of different proteins: enzymes that make new molecules and catalyze nearly all chemical processes in cells; structural components that give cells their shape and help them move; hormones that transmit signals throughout the body; antibodies that recognize foreign molecules; and transport molecules that carry oxygen. The genetic code carried by DNA is what specifies the order and number of amino acids and, therefore, the shape and function of the protein.

The "Central Dogma"—a fundamental principle of molecular biology—states that genetic information flows from DNA to RNA to protein. Ultimately, however, the genetic code resides in DNA because only DNA is passed from generation to generation. Yet, in the process of making a protein, the encoded information must be faithfully transmitted first to RNA then to protein. Transferring the code from DNA to RNA is a fairly straightforward process calledtranscription. Deciphering the code in the resulting mRNA is a little more complex. It first requires that the mRNA leave the nucleus and associate with a large complex of specialized RNAs and proteins that, collectively, are called the ribosome. Here the mRNA is translated into protein by decoding the mRNA sequence in blocks of three RNA bases, called codons, where each codon specifies a particular amino acid. In this way, the ribosomal complex builds a protein one amino acid at a time, with the order of amino acids determined precisely by the order of the codons in the mRNA.

In 1961, Marshall Nirenberg and Heinrich Matthaei correlated the first codon (UUU) with the amino acid phenylalanine. After that, it was not long before the genetic code for all 20 amino acids was deciphered.

A given amino acid can have more than one codon. These redundant codons usually differ at the third position. For example, the amino acid serine is encoded by UCU, UCC, UCA, and/or UCG. This redundancy is key to accommodating mutations that occur naturally as DNA is replicated and new cells are produced. By allowing some of the random changes in DNA to have no effect on the ultimate protein sequence, a sort of genetic safety net is created. Some codons do not code for an amino acid at all but instruct the ribosome when to stop adding new amino acids.

Table 1. RNA triplet codons and their corresponding amino acids.   U C A G U UUU Phenylalanine UUC Phenylalanine UUA Leucine UUG Leucine UCU Serine UCC Serine UCA Serine UCG Serine UAU Tyrosine UAC Tyrosine UAA Stop UAG Stop UGU Cysteine UGC Cysteine UGA Stop UGG Tryptophan C CUU Leucine CUC Leucine CUA Leucine CUG Leucine CCU Proline CCC Proline CCA Proline CCG Proline CAU Histidine CAC Histidine CAA Glutamine CAG Glutamine CGU Arginine CGC Arginine CGA Arginine CGG Arginine A AUU Isoleucine AUC Isoleucine AUA Isoleucine AUG Methionine ACU Threonine ACC Threonine ACA Threonine ACG Threonine AAU Asparagine AAC Asparagine AAA Lysine AAG Lysine AGU Serine AGC Serine AGA Arginine AGG Arginine G GUU Valine GUC Valine GUA Valine GUG Valine GCU Alanine GCC Alanine GCA Alanine GCG Alanine GAU Aspartate GAC Aspartate GAA Glutamate GAG Glutamate GGU Glycine GGC Glycine GGA Glycine GGG Glycine

A translation chart of the 64 RNA codons.

The Core Gene Sequence: Introns and Exons Genes make up about 1 percent of the total DNA in our genome. In the human genome, the coding portions of a gene, called exons, are interrupted by intervening sequences, called introns. In addition, a eukaryotic gene does not code for a protein in one continuous stretch of DNA. Both exons and introns are"transcribed" into mRNA, but before it is transported to the ribosome, the primary mRNA transcript is edited. This editing process removes the introns, joins the exons together, and adds unique features to each end of the transcript to make a "mature"mRNA. One might then ask what the purpose of an intron is if it is spliced out after it is transcribed? It is still unclear what all the functions of introns are, but scientists believe that some serve as the site for recombination, the process by which progeny derive a combination of genes different from that of either parent, resulting in novel genes with new combinations of exons, the key to evolution.

Figure 2. Recombination. Recombination involves pairing between complementary strands of two parental duplex DNAs (top and middle panel). This process creates a stretch of hybrid DNA (bottom panel) in which the single strand of one duplex is paired with its complement from the other duplex.

Gene Prediction Using Computers When the complete mRNA sequence for a gene is known, computer programs are used to align the mRNA sequence with the appropriate region of the genomic DNA sequence. This provides a reliable indication of the beginning and end of the coding region for that gene. In the absence of a complete mRNA sequence, the boundaries can be estimated by ever-improving, but still inexact, gene prediction software. The problem is the lack of a single sequence pattern that indicates the beginning or end of a eukaryotic gene. Fortunately, the middle of a gene, referred to as the core gene sequence--has enough consistent features to allow more reliable predictions.

From Genes to Proteins: Start to Finish

We just discussed that the journey from DNA to mRNA to protein requires that a cell identify where a gene begins and ends. This must be done both during the transcription and the translation process.

Transcription Transcription, the synthesis of an RNA copy from a sequence of DNA, is carried out by an enzyme called RNA polymerase. This molecule has the job of recognizing the DNA sequence where transcription is initiated, called the promoter site. In general, there are two "promoter" sequences upstream from the beginning of every gene. The location and base sequence of each promoter site vary for prokaryotes (bacteria) and eukaryotes (higher organisms), but they are both recognized by RNA polymerase, which can then grab hold of the sequence and drive the production of an mRNA. Eukaryotic cells have three different RNA polymerases, each recognizing three classes of genes. RNA polymerase II is responsible for synthesis of mRNAs from protein-coding genes. This polymerase requires a sequence resembling TATAA, commonly referred to as the TATA box, which is found 25-30 nucleotides upstream of the beginning of the gene, referred to as the initiator sequence. Transcription terminates when the polymerase stumbles upon a termination, or stop signal. In eukaryotes, this process is not fully understood. Prokaryotes, however, tend to have a short region composed of G's and C's that is able to fold in on itself and form complementary base pairs, creating a stem in the new mRNA. This stem then causes the polymerase to trip and release the nascent, or newly formed, mRNA.

Translation The beginning of translation, the process in which the genetic code carried by mRNA directs the synthesis of proteins from amino acids, differs slightly for prokaryotes and eukaryotes, although both processes always initiate at a codon for methionine. For prokaryotes, the ribosome recognizes and attaches at the sequence AGGAGGU on the mRNA, called the Shine-Delgarno sequence, that appears just upstream from the methionine (AUG) codon. Curiously, eukaryotes lack this recognition sequence and simply initiate translation at the amino acid methionine, usually coded for by the bases AUG, but sometimes GUG. Translation is terminated for both prokaryotes and eukaryotes when the ribosome reaches one of the three stop codons.

Structural Genes, Junk DNA, and Regulatory Sequences Over 98 percent of the genome is of unknown function. Although often referred to as "junk" DNA, scientists are beginning to uncover the function of many of these intergenic sequences—the DNA found between genes. Structural Genes Sequences that code for proteins are called structural genes. Although it is true that proteins are the major components of structural elements in a cell, proteins are also the real workhorses of the cell. They perform such functions as transporting nutrients into the cell; synthesizing new DNA, RNA, and protein molecules; and transmitting chemical signals from outside to inside the cell, as well as throughout the cell—both critical to the process of making proteins.

Regulatory Sequences A class of sequences called regulatory sequences makes up a numerically insignificant fraction of the genome but provides critical functions. For example, certain sequences indicate the beginning and end of genes, sites for initiating replication and recombination, or provide landing sites for proteins that turn genes on and off. Like structural genes, regulatory sequences are inherited; however, they are not commonly referred to as genes.

Other DNA Regions Forty to forty-five percent of our genome is made up of short sequences that are repeated, sometimes hundreds of times. There are numerous forms of this "repetitive DNA", and a few have known functions, such as stabilizing the chromosome structure or inactivating one of the two X chromosomes in developing females, a process called X-inactivation. The most highly repeated sequences found so far in mammals are called "satellite DNA"because their unusual composition allows them to be easily separated from other DNA. These sequences are associated with chromosome structure and are found at the centromeres (or centers) and telomeres (ends) of chromosomes. Although they do not play a role in the coding of proteins, they do play a significant role in chromosome structure, duplication, and cell division. The highly variable nature of these sequences makes them an excellent"marker" by which individuals can be identified based on their unique pattern of their satellite DNA.

Figure 3. A chromosome. A chromosome is composed of a very long molecule of DNA and associated proteins that carry hereditary information. The centromere, shown at the center of this chromosome, is a specialized structure that appears during cell division and ensures the correct distribution of duplicated chromosomes to daughter cells. Telomeres are the structures that seal the end of a chromosome. Telomeres play a critical role in chromosome replication and maintenance by counteracting the tendency of the chromosome to otherwise shorten with each round of replication.

Another class of non-coding DNA is the "pseudogene", so named because it is believed to be a remnant of a real gene that has suffered mutations and is no longer functional. Pseudogenes may have arisen through the duplication of a functional gene, followed by inactivation of one of the copies. Comparing the presence or absence of pseudogenes is one method used by evolutionary geneticists to group species and to determine relatedness. Thus, these sequences are thought to carry a record of our evolutionary history.

How Many Genes Do Humans Have?

In February 2001, two largely independent draft versions of the human genome were published. Both studies estimated that there are 30,000 to 40,000 genes in the human genome, roughly one-third the number of previous estimates. More recently scientists estimated that there are less than 30,000 human genes. However, we still have to make guesses at the actual number of genes, because not all of the human genome sequence is annotated and not all of the known sequence has been assigned a particular position in the genome. So, how do scientists estimate the number of genes in a genome? For the most part, they look for tell-tale signs of genes in a DNA sequence. These include: open reading frames, stretches of DNA, usually greater than 100 bases, that are not interrupted by a stop codon such as TAA, TAG or TGA; start codons such as ATG; specific sequences found at splice junctions, a location in the DNA sequence where RNA removes the non-coding areas to form a continuous gene transcript for translation into a protein; and gene regulatory sequences. This process is dependent on computer programs that search for these patterns in various sequence databases and then make predictions about the existence of a gene.

From One Gene–One Protein to a More Global Perspective Only a small percentage of the 3 billion bases in the human genome becomes an expressed gene product. However, of the approximately 1 percent of our genome that is expressed, 40 percent is alternatively spliced to produce multiple proteins from a single gene. Alternative splicing refers to the cutting and pasting of the primary mRNA transcript into various combinations of mature mRNA. Therefore the one gene–one protein theory, originally framed as "one gene–one enzyme", does not precisely hold. With so much DNA in the genome, why restrict transcription to a tiny portion, and why make that tiny portion work overtime to produce many alternate transcripts? This process may have evolved as a way to limit the deleterious effects of mutations. Genetic mutations occur randomly, and the effect of a small number of mutations on a single gene may be minimal. However, an individual having many genes each with small changes could weaken the individual, and thus the species. On the other hand, if a single mutation affects several alternate transcripts at once, it is more likely that the effect will be devastating—the individual may not survive to contribute to the next generation. Thus, alternate transcripts from a single gene could reduce the chances that a mutated gene is transmitted.

Gene Switching: Turning Genes On and Off The estimated number of genes for humans, less than 30,000, is not so different from the 25,300 known genes of Arabidopsis thaliana, commonly called mustard grass. Yet, we appear, at least at first glance, to be a far more complex organism. A person may wonder how this increased complexity is achieved. One answer lies in the regulatory system that turns genes on and off. This system also precisely controls the amount of a gene product that is produced and can further modify the product after it is made. This exquisite control requires multiple regulatory input points. One very efficient point occurs at transcription, such that an mRNA is produced only when a gene product is needed. Cells also regulate gene expression by post-transcriptional modification; by allowing only a subset of the mRNAs to go on to translation; or by restricting translation of specific mRNAs to only when the product is needed. At other levels, cells regulate gene expression through DNA folding, chemical modification of the nucleotide bases, and intricate "feedback mechanisms" in which some of the gene's own protein product directs the cell to cease further protein production.

Controlling Transcription

Promoters and Regulatory Sequences Transcription is the process whereby RNA is made from DNA. It is initiated when an enzyme, RNA polymerase, binds to a site on the DNA called a promoter sequence. In most cases, the polymerase is aided by a group of proteins called "transcription factors" that perform specialized functions, such as DNA sequence recognition and regulation of the polymerase's enzyme activity. Other regulatory sequences include activators, repressors, and enhancers. These sequences can be cis-acting (affecting genes that are adjacent to the sequence) or trans-acting (affecting expression of the gene from a distant site), even on another chromosome.

The Globin Genes: An Example of Transcriptional Regulation An example of transcriptional control occurs in the family of genes responsible for the production of globin. Globin is the protein that complexes with the iron-containing heme molecule to make hemoglobin. Hemoglobin transports oxygen to our tissues via red blood cells. In the adult, red blood cells do not contain DNA for making new globin; they are ready-made with all of the hemoglobin they will need. During the first few weeks of life, embryonic globin is expressed in the yolk sac of the egg. By week five of gestation, globin is expressed in early liver cells. By birth, red blood cells are being produced, and globin is expressed in the bone marrow. Yet, the globin found in the yolk is not produced from the same gene as is the globin found in the liver or bone marrow stem cells. In fact, at each stage of development, different globin genes are turned on and off through a process of transcriptional regulation called "switching". To further complicate matters, globin is made from two different protein chains: an alpha-like chain coded for on chromosome 16; and a beta-like chain coded for on chromosome 11. Each chromosome has the embryonic, fetal, and adult form lined up on the chromosome in a sequential order for developmental expression. The developmentally regulated transcription of globin is controlled by a number of cis-acting DNA sequences, and although there remains a lot to be learned about the interaction of these sequences, one known control sequence is an enhancer called the Locus Control Region (LCR). The LCR sits far upstream on the sequence and controls the alpha genes on chromosome 16. It may also interact with other factors to determine which alpha gene is turned on. Thalassemias are a group of diseases characterized by the absence or decreased production of normal globin, and thus hemoglobin, leading to decreased oxygen in the system. There are alpha and beta thalassemias, defined by the defective gene, and there are variations of each of these, depending on whether the embryonic, fetal, or adult forms are affected and/or expressed. Although there is no known cure for the thalassemias, there are medical treatments that have been developed based on our current understanding of both gene regulation and cell differentiation. Treatments include blood transfusions, iron chelators, and bone marrow transplants. With continuing research in the areas of gene regulation and cell differentiation, new and more effective treatments may soon be on the horizon, such as the advent of gene transfer therapies.

The Influence of DNA Structure and Binding Domains Sequences that are important in regulating transcription do not necessarily code for transcription factors or other proteins. Transcription can also be regulated by subtle variations in DNA structure and by chemical changes in the bases to which transcription factors bind. As stated previously, the chemical properties of the four DNA bases differ slightly, providing each base with unique opportunities to chemically react with other molecules. One chemical modification of DNA, called methylation, involves the addition of a methyl group (-CH3). Methylation frequently occurs at cytosine residues that are preceded by guanine bases, oftentimes in the vicinity of promoter sequences. The methylation status of DNA often correlates with its functional activity, where inactive genes tend to be more heavily methylated. This is because the methyl group serves to inhibit transcription by attracting a protein that binds specifically to methylated DNA, thereby interfering with polymerase binding. Methylation also plays an important role ingenomic imprinting, which occurs when both maternal and paternal alleles are present but only one allele is expressed while the other remains inactive. Another way to think of genomic imprinting is as "parent of origin differences" in the expression of inherited traits. Considerable intrigue surrounds the effects of DNA methylation, and many researchers are working to unlock the mystery behind this concept.

Controlling Translation

Translation is the process whereby the genetic code carried by an mRNA directs the synthesis of proteins. Translational regulationoccurs through the binding of specific molecules, called repressor proteins, to a sequence found on an RNA molecule. Repressor proteins prevent a gene from being expressed. As we have just discussed, the default state for a gene is that of being expressed via the recognition of its promoter by RNA polymerase. Close to the promoter region is another cis-acting site called the operator, the target for the repressor protein. When the repressor protein binds to the operator, RNA polymerase is prevented from initiating transcription, and gene expression is turned off. Translational control plays a significant role in the process of embryonic development and cell differentiation. Upon fertilization, an egg cell begins to multiply to produce a ball of cells that are all the same. At some point, however, these cells begin to differentiate, or change into specific cell types. Some will become blood cells or kidney cells, whereas others may become nerve or brain cells. When all of the cells formed are alike, the same genes are turned on. However, once differentiation begins, various genes in different cells must become active to meet the needs of that cell type. In some organisms, the egg houses store immature mRNAs that become translationally active only after fertilization. Fertilization then serves to trigger mechanisms that initiate the efficient translation of mRNA into proteins. Similar mechanisms serve to activate mRNAs at other stages of development and differentiation, such as when specific protein products are needed.

Mechanisms of Genetic Variation and Heredity

Does Everyone Have the Same Genes? When you look at the human species, you see evidence of a process called genetic variation, that is, there are immediately recognizable differences in human traits, such as hair and eye color, skin pigment, and height. Then there are the not so obvious genetic variations, such as blood type. These expressed, or phenotypic, traits are attributable to genotypic variation in a person's DNA sequence. When two individuals display different phenotypes of the same trait, they are said to have two different alleles for the same gene. This means that the gene's sequence is slightly different in the two individuals, and the gene is said to be polymorphic, "poly" meaning many and "morph" meaning shape or form. Therefore, although people generally have the same genes, the genes do not have exactly the same DNA sequence. These polymorphic sites influence gene expression and also serve as markers for genomic research efforts.

Genetic Variation The cell cycle is the process that a cell undergoes to replicate. Most genetic variation occurs during the phases of the cell cycle when DNA is duplicated. Mutations in the new DNA strand can manifest as base substitutions, such as when a single base gets replaced with another; deletions, where one or more bases are left out; orinsertions, where one or more bases are added. Mutations can either be synonymous, in which the variation still results in a codon for the same amino acid or non-synonymous, in which the variation results in a codon for a different amino acid. Mutations can also cause a frame shift, which occurs when the variation bumps the reference point for reading the genetic code down a base or two and results in loss of part, or sometimes all, of that gene product. DNA mutations can also be introduced by toxic chemicals and, particularly in skin cells, exposure to ultraviolet radiation.

The manner in which a cell replicates differs with the various classes of life forms, as well as with the end purpose of the cell replication. Cells that compose tissues in multicellular organisms typically replicate by organized duplication and spatial separation of their cellular genetic material, a process called mitosis. Meiosis is the mode of cell replication for the formation of sperm and egg cells in plants, animals, and many other multicellular life forms. Meiosis differs significantly from mitosis in that the cellular progeny have their complement of genetic material reduced to half that of the parent cell.

Mutations that occur in somatic cells—any cell in the body except gametes and their precursors—will not be passed on to the next generation. This does not mean, however, that somatic cell mutations, sometimes called acquired mutations, are benign. For example, as your skin cells prepare to divide and produce new skin cells, errors may be inadvertently introduced when the DNA is duplicated, resulting in a daughter cell that contains the error. Although most defective cells die quickly, some can persist and may even become cancerous if the mutation affects the ability to regulate cell growth.

Mutations and the Next Generation There are two places where mutations can be introduced and carried into the next generation. In the first stages of development, a sperm cell and egg cell fuse. They then begin to divide, giving rise to cells that differentiate into tissue-specific cell types. One early type of differentiated cell is the germ line cell, which may ultimately develop into mature gametes. If a mutation occurs in the developing germ line cell, it may persist until that individual reaches reproductive age. Now the mutation has the potential to be passed on to the next generation. Mutations may also be introduced during meiosis, the mode of cell replication for the formation of sperm and egg cells. In this case, the germ line cell is healthy, and the mutation is introduced during the actual process of gamete replication. Once again, the sperm or egg will contain the mutation, and during the reproductive process, this mutation may then be passed on to the offspring. One should bear in mind that not all mutations are bad. Mutations also provide a species with the opportunity to adapt to new environments, as well as to protect a species from new pathogens. Mutations are what lie behind the popular saying of "survival of the fittest", the basic theory of evolution proposed by Charles Darwin in 1859. This theory proposes that as new environments arise, individuals carrying certain mutations that enable an evolutionary advantage will survive to pass this mutation on to its offspring. It does not suggest that a mutation is derived from the environment, but that survival in that environment is enhanced by a particular mutation. Some genes, and even some organisms, have evolved to tolerate mutations better than others. For example, some viral genes are known to have high mutation rates. Mutations serve the virus well by enabling adaptive traits, such as changes in the outer protein coat so that it can escape detection and thereby destruction by the host's immune system. Viruses also produce certain enzymes that are necessary for infection of a host cell. A mutation within such an enzyme may result in a new form that still allows the virus to infect its host but that is no longer blocked by an anti-viral drug. This will allow the virus to propagate freely in its environment.

Mendel's Laws—How We Inherit Our Genes In 1866, Gregor Mendel studied the transmission of seven different pea traits by carefully test-crossing many distinct varieties of peas. Studying garden peas might seem trivial to those of us who live in a modern world of cloned sheep and gene transfer, but Mendel's simple approach led to fundamental insights into genetic inheritance, known today as Mendel's Laws. Mendel did not actually know or understand the cellular mechanisms that produced the results he observed. Nonetheless, he correctly surmised the behavior of traits and the mathematical predictions of their transmission, the independent segregation of alleles during gamete production, and the independent assortment of genes. Perhaps as amazing as Mendel's discoveries was the fact that his work was largely ignored by the scientific community for over 30 years!

Mendel's Principles of Genetic Inheritance Law of Segregation: Each of the two inherited factors (alleles) possessed by the parent will segregate and pass into separate gametes (eggs or sperm) during meiosis, which will each carry only one of the factors. Law of Independent Assortment: In the gametes, alleles of one gene separate independently of those of another gene, and thus all possible combinations of alleles are equally probable. Law of Dominance: Each trait is determined by two factors (alleles), inherited one from each parent. These factors each exhibit a characteristic dominant, co-dominant, or recessive expression, and those that are dominant will mask the expression of those that are recessive.

How Does Inheritance Work? Our discussion here is restricted to sexually reproducing organisms where each gene in an individual is represented by two copies, called alleles—one on each chromosome pair. There may be more than two alleles, or variants, for a given gene in a population, but only two alleles can be found in an individual. Therefore, the probability that a particular allele will be inherited is 50:50, that is, alleles randomly and independently segregate into daughter cells, although there are some exceptions to this rule. The term diploid describes a state in which a cell has two sets of homologous chromosomes, or two chromosomes that are the same. The maturation of germ line stem cells into gametes requires the diploid number of each chromosome be reduced by half. Hence, gametes are said to be haploid—having only a single set of homologous chromosomes. This reduction is accomplished through a process called meiosis, where one chromosome in a diploid pair is sent to each daughter gamete. Human gametes, therefore, contain 23 chromosomes, half the number of somatic cells—all the other cells of the body. Because the chromosome in one pair separates independently of all other chromosomes, each new gamete has the potential for a totally new combination of chromosomes. In humans, the independent segregation of the 23 chromosomes can lead to as many as 16 to 17 million different combinations in one individual's gametes. Only one of these gametes will combine with one of the nearly 17 million possible combinations from the other parent, generating a staggering potential for individual variation. Yet, this is just the beginning. Even more variation is possible when you consider the recombination between sections of chromosomes during meiosis as well as the random mutation that can occur during DNA replication. With such a range of possibilities, it is amazing that siblings look so much alike!

Expression of Inherited Genes Gene expression, as reflected in an organism's phenotype, is based on conditions specific for each copy of a gene. As we just discussed, for every human gene there are two copies, and for every gene there can be several variants or alleles. If both alleles are the same, the gene is said to be homozygous. If the alleles are different, they are said to be heterozygous. For some alleles, their influence on phenotype takes precedence over all other alleles. For others, expression depends on whether the gene appears in the homozygous or heterozygous state. Still other phenotypic traits are a combination of several alleles from several different genes. Determining the allelic condition used to be accomplished solely through the analysis of pedigrees, much the way Mendel carried out his experiments on peas. However, this method can leave many questions unanswered, particularly for traits that are a result of the interaction between several different genes. Today, molecular genetic techniques exist that can assist researchers in tracking the transmission of traits by pinpointing the location of individual genes, identifying allelic variants, and identifying those traits that are caused by multiple genes.

The Nature of Alleles A dominant allele is an allele that is almost always expressed, even if only one copy is present. Dominant alleles express their phenotype even when paired with a different allele, that is, when heterozygous. In this case, the phenotype appears the same in both the heterozygous and homozygous states. Just how the dominant allele overshadows the other allele depends on the gene, but in some cases the dominant gene produces a gene product that the other allele does not. Well-known dominant alleles occur in the human genes for Huntington disease, a form of dwarfism called achondroplasia, and polydactylism (extra fingers and toes). On the other hand, a recessive allele will be expressed only if there are two identical copies of that allele, or for a male, if one copy is present on the X chromosome. The phenotype of a recessive allele is only seen when both alleles are the same. When an individual has one dominant allele and one recessive allele, the trait is not expressed because it is overshadowed by the dominant allele. The individual is said to be a carrier for that trait. Examples of recessive disorders in humans include sickle cell anemia, Tay-Sachs disease, and phenylketonuria (PKU). A particularly important category of genetic linkage has to do with the X and Y sex chromosomes. These chromosomes not only carry the genes that determine male and female traits, but also those for some other characteristics as well. Genes that are carried by either sex chromosome are said to be sex linked. Men normally have an X and a Y combination of sex chromosomes, whereas women have two X's. Because only men inherit Y chromosomes, they are the only ones to inherit Y-linked traits. Both men and women can have X-linked traits because both inherit X chromosomes. X-linked traits not related to feminine body characteristics are primarily expressed in the phenotype of men. This is because men have only one X chromosome. Subsequently, genes on that chromosome that do not code for gender are expressed in the male phenotype, even if they are recessive. In women, a recessive allele on one X chromosome is often masked in their phenotype by a dominant normal allele on the other. This explains why women are frequently carriers of X-linked traits but more rarely have them expressed in their own phenotypes. In humans, at least 320 genes are X-linked. These include the genes for hemophilia, red–green color blindness, and congenital night blindness. There are at least a dozen Y-linked genes, in addition to those that code for masculine physical traits. It is now known that one of the X chromosomes in the cells of human females is completely, or mostly, inactivated early in embryonic life. This is a normal self-preservation action to prevent a potentially harmful double dose of genes. Recent research points to the "Xist" gene on the X chromosome as being responsible for a sequence of events that silences one of the X chromosomes in women. The inactivated X chromosomes become highly compacted structures known as Barr bodies. The presence of Barr bodies has been used at international sport competitions as a test to determine whether an athlete is a male or a female.

Exceptions to Mendel's Laws There are many examples of inheritance that appear to be exceptions to Mendel's laws. Usually, they turn out to represent complex interactions among various allelic conditions. For example,co-dominant alleles both contribute to a phenotype. Neither is dominant over the other. Control of the human blood group system provides a good example of co-dominant alleles.

The Four Basic Blood Types There are four basic blood types, and they are O, A, B, and AB. We know that our blood type is determined by the "alleles" that we inherit from our parents. For the blood type gene, there are three basic blood type alleles: A, B, and O. We all have two alleles, one inherited from each parent. The possible combinations of the three alleles are OO, AO, BO, AB, AA, and BB. Blood types A and B are "co-dominant" alleles, whereas O is "recessive". A codominant allele is apparent even if only one is present; a recessive allele is apparent only if two recessive alleles are present. Because blood type O is recessive, it is not apparent if the person inherits an A or B allele along with it. So, the possible allele combinations result in a particular blood type in this way: OO = blood type O AO = blood type A BO = blood type B AB = blood type AB AA = blood type A BB = blood type B You can see that a person with blood type B may have a B and an O allele, or they may have two B alleles. If both parents are blood type B and both have a B and a recessive O, then their children will either be BB, BO, or OO. If the child is BB or BO, they have blood type B. If the child is OO, he or she will have blood type O.

Pleiotropism, or pleotrophy, refers to the phenomenon in which a single gene is responsible for producing multiple, distinct, and apparently unrelated phenotypic traits, that is, an individual can exhibit many different phenotypic outcomes. This is because the gene product is active in many places in the body. An example isMarfan's syndrome, where there is a defect in the gene coding for a connective tissue protein. Individuals with Marfan's syndrome exhibit abnormalities in their eyes, skeletal system, and cardiovascular system. Some genes mask the expression of other genes just as a fully dominant allele masks the expression of its recessive counterpart. A gene that masks the phenotypic effect of another gene is called anepistatic gene; the gene it subordinates is the hypostatic gene. The gene for albinism in humans is an epistatic gene. It is not part of the interacting skin-color genes. Rather, its dominant allele is necessary for the development of any skin pigment, and its recessive homozygous state results in the albino condition, regardless of how many other pigment genes may be present. Because of the effects of an epistatic gene, some individuals who inherit the dominant, disease-causing gene show only partial symptoms of the disease. Some, in fact, may show no expression of the disease-causing gene, a condition referred to asnonpenetrance. The individual in whom such a nonpenetrant mutant gene exists will be phenotypically normal but still capable of passing the deleterious gene on to offspring, who may exhibit the full-blown disease. Then we have traits that are multigenic, that is, they result from the expression of several different genes. This is true for human eye color, in which at least three different genes are responsible for determining eye color. A brown/blue gene and a central brown gene are both found on chromosome 15, whereas a green/blue gene is found on chromosome 19. The interaction between these genes is not well understood. It is speculated that there may be other genes that control other factors, such as the amount of pigment deposited in the iris. This multigenic system explains why two blue-eyed individuals can have a brown-eyed child. Speaking of eye color, have you ever seen someone with one green eye and one brown eye? In this case, somatic mosaicism may be the culprit. This is probably easier to describe than explain. In multicellular organisms, every cell in the adult is ultimately derived from the single-cell fertilized egg. Therefore, every cell in the adult normally carries the same genetic information. However, what would happen if a mutation occurred in only one cell at the two-cell stage of development? Then the adult would be composed of two types of cells: cells with the mutation and cells without. If a mutation affecting melanin production occurred in one of the cells in the cell lineage of one eye but not the other, then the eyes would have different genetic potential for melanin synthesis. This could produce eyes of two different colors. Penetrance refers to the degree to which a particular allele is expressed in a population phenotype. If every individual carrying a dominant mutant gene demonstrates the mutant phenotype, the gene is said to show complete penetrance.

Molecular Genetics: The Study of Heredity, Genes, and DNA As we have just learned, DNA provides a blueprint that directs all cellular activities and specifies the developmental plan of multicellular organisms. Therefore, an understanding of DNA, gene structure, and function is fundamental for an appreciation of the molecular biology of the cell. Yet, it is important to recognize that progress in any scientific field depends on the availability of experimental tools that allow researchers to make new scientific observations and conduct novel experiments. The last section of the genetic primer concludes with a discussion of some of the laboratory tools and technologies that allow researchers to study cells and their DNA.

Structure of the Double Helix

Double helix is the description of the structure of a DNA molecule. A DNA molecule consists of two strands that wind around each other like a twisted ladder. Each strand has a backbone made of alternating groups of sugar (deoxyribose) and phosphate groups. Attached to each sugar is one of four bases: adenine (A), cytosine (C), guanine (G), or thymine (T). The two strands are held together by bonds between the bases, adenine forming a base pair with thymine, and cytosine forming a base pair with guanine.

What are Stem Cells?

Stem cells are cells found in most, if not all, multi-cellular organisms. They are characterized by the ability to renew themselves through mitotic cell division and differentiating into a diverse range of specialized cell types. Research in the stem cell field grew out of findings by Canadian scientists Ernest A. McCulloch and James E. Till in the 1960s.

Stem cells (center ones) can develop into any cell type. They are valuable as research tools and might, in the future, be used to treat a wide range of diseases. Credit: Judith Stoffer

The two broad types of mammalian stem cells are: embryonic stem cells that are isolated from the inner cell mass of blastocysts, and adult stem cells that are found in adult tissues. In a developing embryo, stem cells can differentiate into all of the specialized embryonic tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing specialized cells, but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues.

Stem cells can now be grown and transformed into specialized cells with characteristics consistent with cells of various tissues such as muscles or nerves through cell culture. Highly plastic adult stem cells from a variety of sources, including umbilical cord blood and bone marrow, are routinely used in medical therapies. Embryonic cell lines and autologous embryonic stem cells generated through therapeutic cloning have also been proposed as promising candidates for future therapies.

Stem cell

Stem cells are biological cells found in all multicellular organisms, that can divide (through mitosis) and differentiate into diverse specialized cell types and can self-renew to produce more stem cells. In mammals, there are two broad types of stem cells: embryonic stem cells, which are isolated from the inner cell mass of blastocysts, and adult stem cells, which are found in various tissues. In adult organisms, stem cells andprogenitor cells act as a repair system for the body, replenishing adult tissues. In a developing embryo, stem cells can differentiate into all the specialized cells (these are called pluripotent cells), but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues.

There are three accessible sources of autologous adult stem cells in humans:

1. Bone marrow, which requires extraction by harvesting, that is, drilling into bone (typically the femur or iliac crest),
2. Adipose tissue (lipid cells), which requires extraction by liposuction, and
3. Blood, which requires extraction through pheresis, wherein blood is drawn from the donor (similar to a blood donation), passed through a machine that extracts the stem cells and returns other portions of the blood to the donor.

Stem cells can also be taken from umbilical cord blood just after birth. Of all stem cell types, autologous harvesting involves the least risk. By definition, autologous cells are obtained from one's own body, just as one may bank his or her own blood for elective surgical procedures.

Highly plastic adult stem cells are routinely used in medical therapies, for example in bone marrow transplantation. Stem cells can now be artificially grown and transformed (differentiated) into specialized cell types with characteristics consistent with cells of various tissues such as muscles or nerves through cell culture. Embryonic cell lines and autologous embryonic stem cells generated through therapeutic cloning have also been proposed as promising candidates for future therapies. Research into stem cells grew out of findings by Ernest A. McCulloch and James E. Till at the University of Toronto in the 1960s.

The CELL THEORY

The CELL THEORY, or cell doctrine, states that all organisms are composed of similar units of organization, called cells. The concept was formally articulated in 1839 by Schleiden & Schwann and has remained as the foundation of modern biology. The idea predates other great paradigms of biology including Darwin's theory of evolution (1859), Mendel's laws of inheritance (1865), and the establishment of comparative biochemistry (1940).      Ultrastructural research and modern molecular biology have added many tenets to the cell theory, but it remains as the preeminent theory of biology.  The Cell Theory is to Biology as Atomic Theory is to Physics.

Formulation of the Cell Theory               In 1838, Theodor Schwann and Matthias Schleiden were enjoying after-dinner coffee and talking about their studies on cells. It has been suggested that when Schwann heardSchleiden describe plant cells with nuclei, he was struck by the similarity of these plant cells to cells he had observed in animal tissues. The two scientists went immediately toSchwann's lab to look at his slides. Schwann published his book on animal and plant cells (Schwann 1839) the next year, a treatise devoid of acknowledgments of anyone else's contribution, including that of Schleiden (1838). He summarized his observations into three conclusions about cells:    1)  The cell is the unit of structure, physiology, and organization in living things.    2)  The cell retains a dual existence as a distinct entity and a building block in the                         construction of organisms.    3)  Cells form by free-cell formation, similar to the formation of crystals (spontaneous generation).      We know today that the first two tenets are correct, but the third is clearly wrong.  The correct interpretation of cell formation by division was finally promoted by others and formally enunciated in Rudolph Virchow's powerful dictum, "Omnis cellula e cellula"...  "All cells only arise from pre-existing cells".
The modern tenets of the Cell Theory include:     1. all known living things are made up of cells.    2. the cell is structural & functional unit of all living things.    3. all cells come from pre-existing cells by division.             (Spontaneous Generation does not occur).    4. cells contains hereditary information which is passed from               cell to cell during cell division.    5. All cells are basically the same in chemical composition.    6. all energy flow (metabolism & biochemistry) of life occurs               within cells.
As with any theory, its tenets are based upon previous observations and facts, which are synthesized into a coherent whole via the scientific method. The Cell Theory is no different being founded upon the observations of many.  (Landmarks in the Study of Cells)
Credit for the first compound (more than one lens) microscope is usually given to Zacharias Jansen, of Middleburg, Holland, around the year 1595. Since Jansen was very young at that time, it's possible that his father Hans made the first one, but young Jansen perfected the production. Details about the first Jansen microscopes are not clear, but there is some evidence which allows us to make some guesses about them (Jansen microscopes).
In 1663 an English scientist, Robert Hooke, discovered cells in a piece of cork, which he examined under his primitive microscope (figures). Actually, Hooke only observed cell walls because cork cells are dead and without cytoplasmic contents. Hooke drew the cells he saw and also coined the word CELL. The word cell is derived from the Latin word 'cellula' which means small compartment. Hooke published his findings in his famous work, Micrographia: Physiological Descriptions of Minute Bodies made by Magnifying Glasses (1665).
Ten years later Anton van Leeuwenhoek (1632-1723), a Dutch businessman and a contemporary of Hooke used his own (single lens) monocular microscopes and was the first person to observe bacteria and protozoa. Leeuwenhoek is known to have made over 500 "microscopes," of which fewer than ten have survived to the present day. In basic design, probably all of Leeuwenhoek's instruments were simply powerful magnifying glasses, not compound microscopes of the type used today. Leeuwenhoek's skill at grinding lenses, together with his naturally acute eyesight and great care in adjusting the lighting where he worked, enabled him to build microscopes that magnified over 200 times, with clearer and brighter images than any of his colleagues at that time. In 1673, Leeuwenhoek began writing letters to the newly formed Royal Society of London, describing what he had seen with his lenses. His first letter contained some observations on the stings of bees. For the next fifty years he corresponded with the Royal Society. His observations, written in Dutch, were translated into English or Latin and printed in the Philosophical Transactions of the Royal Society. Leeuwenhoek looked at animal and plant tissues, at mineral crystals, and at fossils. He was the first to see microscopic single celled protists with shells, the foraminifera, which he described as "little cockles. . . no bigger than a coarse sand-grain."  He discovered blood cells, and was the first to see living sperm cells of animals. He discovered microscopic animals such as nematodes (round worms) and rotifers. The list of his discoveries is long. Leeuwenhoek soon became famous as his letters were published and translated.  In 1680 he was elected a full member of the Royal Society. After his death on August 30, 1723, a member of the Royal Society wrote...  "Antony van Leeuwenhoek considered that what is true in natural philosophy can be most fruitfully investigated by the experimental method, supported by the evidence of the senses; for which reason, by diligence and tireless labour he made with his own hand certain most excellent lenses, with the aid of which he discovered many secrets of Nature, now famous throughout the whole philosophical World".   No truer definition of the scientific method may be found.
Between 1680 and the early 1800's it appears that not much was accomplished in the study of cell structure. This may be due to the lack of quality lens for microscopes and the dedication to spend long hours of detailed observation over what microscopes existed at that time. Leeuwenhoek did not record his methodology for grinding quality lenses and thus microscopy suffered for over 100 years.
German natur-philosopher and microscopist, Lorenz Oken  had been trained in medicine at Freiburg University. He went on to become a renown philosopher and thinker of the 19th century.  It is reported that in 1805 Oken stated that "All living organisms originate from and consist of cells"... which may have been the first statement of a cell theory.
Around 1833 Robert Brown reported the discovery of the nucleus. Brown was a naturalist who visited the "colonies of Australia" from 1801 through 1805, where he cataloged and described over 1,700 new species of plants. Brown was an accomplished technician and an extraordinarily gifted observer of microscopic phenomena. It was Brown who identified the naked ovule in the gymnospermae. This is a difficult observation to make even with a modern instrument and the benefit of hindsight. But it was with the observation of the incessant agitation of minute suspended particles that Brown's name became inextricably linked. The effect, since described as Brownian Movement, was first noticed by him in 1827.  Having worked on the ovum, it was natural to direct attention to the structure of pollen and its Brown  interrelationship with the pistil. In the course of his microscopic studies of the epidermis of orchids, discovered in these cells "an opaque spot," which he named the nucleus. Doubtless the same "spot" had been seen often enough before by other observers, butBrown was the first to recognize it as a component part of the vegetable cell and to give it a name. This nucleus (or areola as he called it) of the cell, was not confined to the epidermis, being also found, in the pubescence of the surface and in the parenchyma or internal cells of the tissue. This nucleus of the cell was not confined to only orchids, but was equally manifest in many other monocotyledonous families and in the epidermis of dicotyledonous plants, and even in the early stages of development of the pollen. In some plants, as Tradascantia virginica, it was uncommonly distinct, especially in the tissue of the stigma, in the cells of the ovum, even before impregnation, and in all the stages of formation of the grains of pollen.      It is upon the works of Hooke, Leeuwenhoek, Oken, and Brown that Schleiden and Schwann built their Cell Theory. It was the German professor of botany at the University of Jena, Dr. M. J. Schleiden, who brought the nucleus to popular attention, and to asserted its all-importance in the function of a cell. Schleiden freely acknowledged his indebtedness to Brownfor first knowledge of the nucleus, but he soon carried out his own observations of the nucleus, far beyond those of Brown. He came to believe that the nucleus is really the most important portion of the cell, in that it is the original structure from which the remainder of the cell is developed. He called it the cytoblast. He outlined his views in an epochal paper published in Muller's Archives in 1838, under title of "Beitrage zur Phytogenesis." This paper is in itself of value, yet the most important outgrowth of Schleiden's observations of the nucleus did not spring from his own labors, but from those of a friend to whom he mentioned his discoveries the year previous to their publication. This friend was Dr. Theodor Schwann, professor of physiology in the University of Louvain.      Schwann was puzzling over certain details of animal histology which he could not clearly explain. He had noted a strange resemblance of embryonic cord material, from which the spinal column develops, to vegetable cells. Schwann recognized a cell-like character of certain animal tissues. Schwann felt that this similarity could not be mere coincidence, and it seemed to fit when Schleiden called his attention to the nucleus. Then at once he reasoned that if there really is the correspondence between vegetable and animal tissues that he suspected, and if the nucleus is so important in the vegetable cell as Schleiden believed, the nucleus should also be found in the ultimate particles of animal tissues. A closer study of animal tissues under the microscope showed, in particular in embryonic tissues, that the "opaque spots" that Schleiden described were found in abundance. The location of these nuclei at comparatively regular intervals suggested that they are found in definite compartments of the tissue, as Schleiden had shown to be the case with vegetables; indeed, the walls that separated such cell-like compartments one from another were in some cases visible. Soon Schwann was convinced that his original premise was right, and that all animal tissues are composed of cells not unlike the cells of vegetables. Adopting the same designation, Schwann propounded what soon became famous as the CELL THEORY. So expeditious was his observations that he  published a book early in 1839, only a few months after the appearance of Schleiden's paper.      The main theme of his book was to unify vegetable and animal tissues. Accepting cell-structure as the basis of all vegetable tissues, he sought to show that the same is true of animal tissues.      And by cell Schwann meant, as did Schleiden also, what the word ordinarily implies--a cavity walled in on all sides. He knew that the cell might be filled with fluid contents, but he regarded these as relatively subordinate in importance to the nucleus and cell wall.      Their main thesis, the similarity of development of vegetable and animal tissues and the cellular nature of life, was supported almost immediately by a mass of carefully gathered evidence which a multitude of microscopists confirmed. So Schwann's work became a classic almost from the moment of its publication. Various other workers disputed Schwann's claim to priority of discovery, in particular an English microscopist, Valentin, who asserted that he was working closely along the same lines. So did many others, such as Henle, Turpin, Du-mortier, Purkinje, and Muller, all of whom Schwann himself had quoted in his work. Many physiologists had, earlier than any of the above, foreshadowed the cell theory, including  Kaspar Friedrich Wolff around the close of the previous century, and Treviranus in 1807.      But, as we have seen in the scientific method, it is one thing to foreshadow a discovery, it is quite another to give it full expression and make it the cornerstone of future discoveries. And when Schwann put forward the explicit claim that "there is one universal principle of development for the elementary parts, of organisms, however different, and this principle is the formation of cells," he enunciated a doctrine which was for all practical purposes absolutely new and opened up a novel field for the microscopist to enter. A most important era inCell Biology dates from the publication of his book in 1839.
"Mikroskopische Untersuchungen über die Übereinstimmung in der Struktur und dem Wachstum der Thiere und Pflanzen"       Microscopic Researches on the Conformity in Structure and Growth Between Animals and Plants
For the first 150 years, the cell theory was primarily a structural idea. This structural view, which is found in most textbooks, describes the components of a cell and their fate in cell reproduction. Since the 1950's, however, cell biology has focused on DNA and its informational features. Today we look at the cell as a unit of self-control. ie., the description of a cell must includes ideas about how genetic information is converted to structure.      The cell doctrine reached its present-day eminence in 1896 with the publication of E. B. Wilson's The Cell in Development and Heredity, which was an accumulation of what was known about the roles of cells in embryology and chromosomal behavior.

Landmarks in Study of Cell Biology

1595	Jansen credited with 1st compound microscope                                     SCROLL DOWN
1626	Redi postulated that living things do not arise from spontaneous generation.
1655	Hooke described 'cells' in cork.
1674	Leeuwenhoek discovered protozoa. He saw bacteria some 9 years later.
1833	Brown descibed the cell nucleus in cells of the orchid.
1838	Schleiden and Schwann proposed cell theory.
1840	Albrecht von Roelliker realized that sperm cells and egg cells are also cells.
1856	N. Pringsheim observed how a sperm cell penetrated an egg cell.
1857	Kolliker described mitochondria.
1858	Rudolf Virchow (physician, pathologist and anthropologist) expounds his famous conclusion: omnis cellula e cellula , that is cells develop only from existing cells  [cells come from preexisting cells]
1869	Miescher isolated DNA for the first time.
1879	Flemming described chromosome behavior during mitosis.
1883	Germ cells are haploid, chromosome theory of heredity.
1898	Golgi described the golgi apparatus.
1926	Svedberg developed the first analytical ultracentrifuge.
1938	Behrens used differential centrifugation to separate nuclei from cytoplasm.
1939	Siemens produced the first commercial transmission electron microscope.
1941	Coons used fluorescent labeled antibodies to detect cellular antigens.
1952	Gey and co-workers established a continuous human cell line.
1953	Crick, Wilkins and Watson proposed structure of DNA double-helix.
1955	Eagle systematically defined the nutritional needs of animal cells in culture.
1957	Meselson, Stahl and Vinograd developed density gradient centrifugation in cesium chloride solutions for separating nucleic acids.
1965	Ham introduced a defined serum-free medium. Cambridge Instruments produced the first commercial scanning electron microscope.
1976	Sato and colleagues publish papers showing that different cell lines require different mixtures of hormones and growth factors in serum-free media.
1981	Transgenic mice and fruit flies are produced. Mouse embryonic stem cell line established.
1987	First knockout mouse created.
1998	Mice are cloned from somatic cells.
2000	Human genome DNA sequence draft.

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