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Introduction to Molecular Biology BIOS 302 Northern Illinois University What is Life? • NASA definition: “Life is a chemical system capable of Darwinian evolution”. • The two fundamental principles of life: 1. Life is a complex set of chemical reactions, but there is no fundamental difference between living and non-living material. No “vital principle” that separates life from non-life. • Also implies that studying how living things work means studying the chemical reactions involved. 2. Life evolves through natural selection. Over time, living things become more capable of surviving and reproducing by the process of random mutations followed by interactions with their environment and each other. • By examining a wide range of species we can learn about what mutations have proved useful. The Chemical Reactions of Life • To survive, a cell must do many things: • Homeostasis: maintain a relatively constant internal state different from the outside: pH, ion concentrations, temperature, macromolecule concentrations • Metabolism: take in energy and materials from the outside and convert them into compounds that become part of the organism • Respond to environment to optimize its situation: adapt to external conditions to acquire food and avoid harmful things • Growth and Reproduction: make more copies of itself, passing genetic information to offspring. To accomplish these things: • Separation of living material inside from non-living outside: a cell membrane, composed of lipids. The membrane is hydrophilic (water-loving) on its faces, but hydrophobic on the inside. This creates a barrier that very few molecules can go through without help. • Bring in raw materials and energy from the outside. Raw materials pass through the membrane through protein channels. • Utilize many chemical reactions to convert the raw materials into parts of the organism. • Each reaction needs a separate catalyst: enzymes. Most enzymes are proteins. • Store and transmit information on how to build the necessary proteins: DNA and the processes of gene expression. Membrane Transport • It takes a lot of different proteins to do all the specific processes in a cell. The human genome contains about 25,000 genes. At least 1550 are known to be membrane transporters. • Another very large group of membrane proteins are receptors, which detect specific compounds outside the cell and pass that information into the cell. • About 25% of the human genome is devoted to membrane receptors and transporters. • Just to get a feel for how many proteins are needed for membrane transport, here is a diagram of various types of transporter, using different mechanisms to move some specific compound across the membrane. • This diagram is a partial list of the specific transporters needed to move things across the mitochondrial membrane. • Converting compounds from the outside world (food) into parts of the living cell. This requires many reactions, and each reaction is catalyzed by its own specific enzyme. A small part of the metabolic activities in a cell. Glycolysis is the breaking down of glucose into pyruvate. This generates energy (in the form of ATP) . Also, pyruvate is the raw material for several other necessary compounds in the cell. Metabolic Activities A chart of the main metabolic reactions in human cells. The image needs to be blown up much larger to be readable. There are thousands of reactions shown here. Proteins and DNA • It is clear that the cell needs thousand of different proteins. • Proteins are composed of linear chains of amino acids. There are 20 amino acids in common use. • The type of amino acids and their order in the protein chain determines the folding pattern and the function of the protein. • The 3-dimensional structure of each protein is unique. • Proteins can’t reproduce themselves. • The cell makes the proteins it need by storing information about the amino acid sequence of each protein in its DNA, then using that information to synthesize the proteins. • DNA is a much more regular and simple a molecule than proteins are. All DNA, regardless of what proteins it codes for, is a double helix composed of strands of nucleotide , which contain 4 types of nucleotide. • The simple structure makes DNA easy to replicate, easy to work with during the process of gene expression, and stable for long term storage. • This simple, regular structure also makes DNA easy to manipulate and sequence in the laboratory. • Especially important: if you know the DNA sequence that codes for a protein, you can instantly deduce its amino acid sequence (the genetic code). DNA Gene Expression • The proteins a cell needs are made by the process of gene expression • Gene expression is a 2 step process: • First, the region of DNA that is the gene is copied into RNA. This process is transcription. • Then, information in RNA is converted into the amino acid sequence of proteins (translation) • Also important: to reproduce, the cell must make new copies of its DNA. This is the process of replication. • These three processes, replication, transcription, and translation, define the flow of information in the cell. Together, they are called the Central Dogma of Molecular Biology. • A corollary: Information does not flow from protein back to DNA. This is a molecular version of the incorrectness of “inheritance of acquired characteristics”. Changes in proteins do not affect the DNA in a systematic manner (although they can cause random changes in DNA). • This class deals with the molecules of the Central Dogma (DNA, RNA, protein), the processes of replication, transcription and translation (plus supporting processes), and the control of these activities. Evolution Evolution • “Nothing in biology makes sense except in the light of evolution.” • The basic principle of evolution by natural selection: mutations occur randomly, and those mutations that increase evolutionary fitness (the ability to survive and reproduce) tend to spread, because individuals with those mutations outcompete others and end up with more descendants. Mutations • A mutation is any change in the DNA nucleotide sequence. • Some changes are very small: one nucleotide substituted for another. • Other changes are very large: chromosome rearrangements and whole genome duplications, for instance. • Mutations can alter the structure of proteins, as well as the time, place, and amount at which they are produced. • We will study various types of mutation: how they arise and what their effects are. Brief History of Life on Earth • The Universe begins as an incredibly hot dense point that explodes outward: the Big Bang, 13.8 billion years ago • The Earth, the Sun and the rest of our Solar System form from a cloud of gas and dust: 4.6 billion years ago • A period of bombardment by large objects from space keeps Earth’s surface molten for several hundred million years. During this time, many organic molecules are formed: prebiotic chemistry • First evidence of life on Earth is form about 3-3.5 billion years ago. Life has been on Earth through most of its history. • Cyanobacteria evolve a form of photosynthesis that generated oxygen as a waste product. The resulting oxygen poisons many organisms, but allows much more efficient energy production. About 2.5 billion years ago. • Eukaryotes appear, with mitochondria that can use the oxygen, and a much greater diversity of forms than found in prokaryotes, about 1 billion years ago. • Multicellular organisms, with all of today’s major phyla, appear about 600 million years ago (the Cambrian explosion). • Two major mass extinction events: Permian (200 million years ago) and Cretaceous (65 million years ago), plus many smaller mass extinctions, alter the number and distribution of living forms. Prebiotic Chemistry • The evolution of the organisms we see today occurred over a very long time. Here we see a quick look at the origin of life and how things have changed over time. • The main elements in living things: carbon, hydrogen, oxygen, and nitrogen, are among the most common elements in the Universe. • Hydrogen has been here from the beginning. The other elements were formed as part of nuclear fusion in stars. • Many simple organic (carbon-containing) compounds have been detected in outer space, either in meteorites or by the patterns of electromagnetic radiation they absorb and emit. • Heat, pressure, lightning, UV light, and other energy sources created more such compounds (and more complex compounds) in the atmosphere and oceans of the primitive Earth. Origin of Life • There is no scientific consensus about how life began—not even a solid theory, just a number of hypotheses without compelling evidence. • Primordial soup. Organic compounds, including many found in living organisms, can be formed from gases that existed on the primitive Earth by lightning, radiation, or heat. They also are found in comets: organic compounds are very common in outer space as well as on Earth. They were undoubtedly present from the beginning on Earth. • Darwin’s idea, still reasonable today: life may have begun in a "warm little pond, with all sorts of ammonia and phosphoric salts, lights, heat, electricity, etc. present, so that a protein compound was chemically formed ready to undergo still more complex changes….At the present day such matter would be instantly devoured or absorbed, which would not have been the case before living creatures were formed.“ • Deep sea vents (iron-sulfur world). Lots of chemicals that can be used to generate energy, catalysis maybe occurred on iron-sulfur crystals. The idea here is that maybe life started under harsh conditions: high temperatures and pressures, and not in a nice warm little pond. • Lots of other theories. RNA World Hypothesis • RNA molecules are capable of both storing information and catalyzing chemical reactions. In present day cells, DNA stores information and proteins perform catalysis, with RNA as the intermediate between DNA and protein. • One can imagine a time when there was no DNA or protein, just RNA performing both information storage and catalysis: this is the RNA World hypothesis. • Very long ago, at least 3.5-4 billion years ago. (Recall the Earth is 4.6 billion years old, and didn’t have a stable solid surface until about 4 billion years ago). • Presumably there was once a self-replicating RNA molecule. However, no such RNA has been found or made artificially so far. • The RNA World hypothesis is an intriguing concept, but there is very little real evidence for it. But during this course we will occasionally note the central role played by RNA in basic cellular processes. All Cells Have Evolved from a Common Ancestor • We strongly believe all cells all descended from a single primitive organism, the Last Universal Common Ancestor (LUCA). • Probably 3-3.5 billion years ago or so. • Long after the end of the RNA World (if it ever existed) • The LUCA was not the first living cell. It was the cell whose descendants eventually outcompeted all other cells. Lots of other cells and forms of life undoubtedly existed then, but eventually became extinct. • No one has ever found an organism that didn’t fit this model. All Cells Use the Same Basic Chemistry • The main reason we think there was a common ancestor of all living things. • Same macromolecules: proteins, nucleic acids, carbohydrates, and lipids • Same subunits and functions for these macromolecules: • All cells store their information as DNA, using the same 4 nucleotides. • All cells use RNA as an intermediate between DNA and protein, using the same genetic code to translate the sequence of bases into amino acids. • All cells use proteins to do most of the work of the cell, and the proteins all use the same 20 amino acid subunits. Prokaryotes and Eukaryotes • The defining difference between prokaryote and eukaryote is that eukaryotes have their DNA stored in a membranebound nucleus, while prokaryotes have their DNA floating freely in the cytoplasm. • Prokaryotes are single celled organisms that are simpler than eukaryotes. They are also far more diverse in the conditions they grow in and their biochemistry. • Prokaryotes have a single circular chromosome, and very few if any internal membranes or membrane-bound organelles. Transcription of the DNA into RNA and translation of RNA into protein occur simultaneously in a single location. • All large multicellular organisms are eukaryotes: plants, animals, fungi, seaweed, etc. There are also a large and diverse group of single celled eukaryotes (protists). • Eukaryotes have multiple linear chromosomes, internal membranes, and transcription occurs in a separate location from translation. • Much of this course (and BIOS 303) is devoted to eukaryotic biology, but I will try to bring in some prokaryotic things when appropriate. Tree of Life • Evolutionary descent is traced through differences in genes: the more mutational differences that have accumulated between two species, the further back in time their common ancestor lived. Carl Woese, discoverer of the Archaea and the use of 16S RNA in phylogeny • One of the very few genes found in all organisms is the gene for 16S ribosomal RNA. • It is an essential component of the protein synthesis machinery. • Called 18S RNA in eukaryotes • By tracing the accumulation of mutational changes, it is possible to generate a single tree showing the descent of all organisms from a common ancestor. • Biggest surprise: the prokaryotes are divided into 2 very different groups: the Bacteria and the Archaea. • Note how small the branches are for plants, animals and fungi: the organisms we can see are only a tiny part of the diversity of life. • We will look into how changes in DNA have been used to trace the relationships between different species. Three Domains of life: Bacteria, Archaea, and Eukarya Cell Basics The Cell Theory 1. All living organisms are composed of cells. • Note that there are areas in the body that are outside of cells, however 2. The cell is the basic unit of life. • It is the minimum level of complexity that displays all the characteristics of life 3. All cells originate from previously existing cells. The first person to see microorganisms, Anton van Leeuwenhoek, used a powerful (250x) single lens. • Origin of life problem • This theory has been around since the 1830’s. It is well accepted in the scientific community because there has been a lack of any good counterexamples. • Based on microscopic examination of plants, animals, and other organisms. Robert Hooke invented the compound microscope (using 2 lenses): 1665 Cells are Very Diverse (A) Ner e cell in the cerebellum (B) Paramecium (single celled eukaryote) (C) Section of a plant stem (D) Bacterium (Bdellovibrio bacteriovorus) (E) Macrophage (white blood cell) engulfing a red blood cell Unicellular vs. Multicellular • Organisms can be unicellular or multicellular. • Multicellular organisms have many cells, which are differentiated into different cell types, with different functions. • Within the bodies of multicellular organisms there are spaces outside of the cells: the extracellular matrix. • Unicellular organisms perform all the activities of life within a single cell. • There are also colonial organisms, where all the cells have identical (or almost identical) functions, but they are joined together into a unit. Components of Cells • All cells are surrounded by a cell membrane that allows very few things other than water to get in or out without regulation. • All cells contain DNA, which has the instructions to run the cell as well as reproduce it. • All cells contain cytosol, an aqueous semiliquid containing all the chemicals needed to maintain life. • Cytosol is sometimes called cytoplasm, which implies that it is outside the nucleus. • All cells take in food—both materials and an energy source, and convert it to parts of the cell itself. Waste heat and materials are then excreted from the cell. • All cells respond to the environment, seeking out opportunities to live, grow, and reproduce; and avoiding/defending against things that will hurt it. Major themes/concepts in 302 • Molecular biology focusses on storage, expression , and transmission of genetic information: DNA, RNA, protein. • What are the molecules that drive life? • How do shape and structure of molecules relate to function? • How do molecules influence/regulate biological pathways? (Gene expression and regulation) • How do we study molecules?