The Genetic Revolution: 1. Intro, Biological & Chemical Background
-
Upload
biochempiano -
Category
Science
-
view
205 -
download
4
Transcript of The Genetic Revolution: 1. Intro, Biological & Chemical Background
Welcome to
The Genetic Revolution and You
• Please sit only at the tables.
How rapidly advancing genetic and biological knowledge are affecting and will affect your health and well-being and that of future generations
Welcome toThe Genetic Revolution and You
Adult School of Montclair
Fall 2014
Dr. David Reibstein
Created by David Reibstein, Ph.D., for the course
The Genetic Revolution and You: Today and Tomorrow
Fall 2014
Adult School of Montclair
Copyright 2014 David Reibstein
“The notion of the infinite variety of detail and the multiplicity of forms is a pleasing one; in complexity are the fringes of beauty, and in variety are generosity and exuberance.”
‐Annie Dillard, American author, b. 1945
Aims of This Course
1. To describe and clarify modern genetics, and describe its basis in molecular knowledge
2. To show how this knowledge has been acquired
3. To discuss some of the ways in which this knowledge is being used, and might be used in the future, for understanding:
a) the living world
b) the treatment and reduction of disease
c) the extension of healthy life-spans
4. To discuss the ethical, legal, and social implications of current and future developments in genetics.
Outline of the Course1.Overview and Objectives
2.The chemical and biological basis of life and its organization on earth
3.Chemicals of Life: DNA, RNA, and proteins
4.Genes and Genomes: How genes make us what we are
5.The Human Genome Project (HGP) and what we have learned from it
6.How the HGP is leading to new approaches to health care:
a. Finding genes that contribute to disease
b. Resilience to mutations
c. Editing Our Genome
d. Aging
7. Cancer: What genetics tells us
8. The Microbiome – the microbes that live inside you and what they do for you
9. Viral diseases: Influenza, Ebola, 10.A Possible Future:
a) “Designer Children”b) “Personalized Medicine”
Along the way, you and I will discuss the ethical, legal, and social issues that arise from these developments.
The format of these discussions will vary depending on the topic.
Along the way, you and I will discuss the ethical, legal, and social issues that arise from these developments.
I welcome questions that seek clarification.
• However, I may choose to address the question after class if I think the answer is complicated, or I judge it to be not of interest to everyone, or not completely relevant to the course. (I enjoy talking about anything with anyone!)
Let’s start with 2 questions
1. What is the “Genetic Revolution?”
–Knowledge about the organization of human genes has opened up wide areas of research, which will affect:
• Health care
• Reproduction
• Life spans
What kinds of knowledge?
• How the structure of DNA contains instructions for making and regulating an organism
• How mutations (changes in DNA)have affected evolution and howthey affect our health.
• Human genetic variation
What kinds of knowledge?
• The Human Genome Project - Launched 1990, completed 2003:
– the complete sequence of human DNA,
which is leading to:
–A fuller understanding of how our genetic machinery operates.
Some important points in the history of genetics
1856-1865 Gregor Mendel’s experiments with peas show that inheritance obeys simple rules. His work was largely ignored
1859 Charles Darwin: On the Origin of Species
1944 DNA is shown to be the genetic material, and to consist of a string of 4 bases
1953 Structure of DNA shown to be a double helix: Watson & Crick with data from Rosalind Franklin
1956 DNA shown to be organized into 23 pairs of chromosomes in humans
1956 Mechanism of duplication of DNA worked out
1977 Fred Sanger and colleagues work out method for sequencing DNA
2003 Completion of Human Genome Project
The Second Question
2. Why does it make sense to say “Every disease has a genetic component?” What does that mean, and how can this be true?
“All diseases have a genetic component.”
Eric D. Green, M.D., Ph.D., Director of the National Human Genome Research Institute (NHGRI) at the
National Institutes of Health (NIH)
What does this mean exactly? And how can this be true?
Let’s begin with a quote that I used in the descriptive paragraph on the Adult
School web site.
What is a gene?
• A gene is a segment of DNA.
• Genes can have one of two functions:
– Structural genes: carry the code for one or more proteins.
–Regulatory genes: regulate processes in the organism.
• A gene is the molecular unit of heredity.
What do regulatory genes do?
• Some code for proteins that regulate body processes.
• Some are sites of recognition for other molecules that regulate the production of other proteins.
Genes regulating other genes
These controls can be very complex.
A regulatory gene controls the function of other genes in the same way as a TV remote controls a television.
Schematic example
An example of a regulator gene
1. Regulator gene…
2. makes repressor protein, …
3. which regulates another gene
Genetic components of disease:Diseases can be divided into two categories
1. Monogenic diseases: rare, catastrophic diseases caused by a single gene variant, such as cystic fibrosis.
– For 127 such diseases, we presently know of 164 genes harboring 685 known variants.
2. Most common diseases are due to multiple genes. For example, inflammatory bowel disease, rheumatoid arthritis, type 1 diabetes, cancer, Alzheimer’s disease, schizophrenia, and asthma.
– Thousands of variants spanning many hundreds of genes have now been associated with these diseases.
54 monogenic diseases can be detected by Preimplantation Genetic Diagnosis
• Achondroplasia• Adrenoleukodystrophy• Alpha thalassaemia• Alpha-1-antitrypsin deficiency• Alport syndrome• Amyotrophic lateral sclerosis• Beta thalassemia• Charcot-Marie-Tooth• Congenital disorder of
glycosylation type 1a• Crouzon syndrome• Cystic fibrosis• Duchenne and Becker muscular
dystrophy• Dystonia 1, Torsion• Emery-Dreifuss muscular
dystrophy• Facioscapulohumeral dystrophy• Familial adenomatous polyposis• Familial amyloidotic
polyneuropathy• Familial dysautonomia• Fanconi anaemia
• Fragile X• Glutaric aciduria type 1• Haemophilia A and B• Hemophagocytic
lymphohistiocytosis• Holt-Oram syndrome• Huntington's disease• Hyperinsulinemic hypoglycemia• Hypokalaemic periodic paralysis• Incontinentia pigmenti• Lynch syndrome• Marfan syndrome• Menkes disease• Metachromatic leukodystrophy• Mucopolysaccharidosis type II
(Hunter syndrome)• Multiple endocrine neoplasia
(MEN2)• Multiple exostosis• Myotonic dystrophy• Neurofibromatosis type I and II• Non-syndromic Sensorineural
Deafness
• Norrie syndrome• Osteogenesis imperfecta (brittle
bone disease)• Polycystic kidney, autosomal
dominant• Polycystic kidney, autosomal
recessive• Pompe's syndrome• Sickle cell anaemia• Smith-Lemli-Opitz syndrome• Spastic paraplegia 4• Spinal and bulbar muscular
atrophy• Spinal muscular atrophy• Spinocerebellar ataxia 1, 2 and 3• Spondylometaphyseal dysplasia
(Schmidt)• Tay-Sachs disease• Treacher Collins• Tuberous sclerosis• Von Hippel-Lindau syndrome
And while we’re on the subject of genes:
• What is DNA?
• For now, let’s just note that DNA is a molecule that contains all the information for constructing and regulating an organism.
– Instructions for making proteins
– Instructions that guide and regulate:
• Our development from conception
• Our growth
• Our functioning
The Old Way of Classifying Life
Animals
Plants
But it turned out that life is more complicated than that
Let’s look a little closer
Us
First living organism – probably at least 2 – 3.5 billion years ago
Split between animals and plants happened more than 1 billion years ago.
Before we go any further, let’s get acquainted with the relative sizes
of things
How small are molecules?
• An 8-ounce glass of water contains on the order of 1023 H2O molecules.
• That is
100,000,000,000,000,000,000,000million
million
million
million
Flea
Amoeba: 200 micrometers = 0.2 mm
Eukaryotic cell
Large virus 200 nm = 0.2 μm
Cell membrane (L)Small virus (R)
DNA : 2 nanometers =2
1000micrometer
Mitochondria (L)Bacteria (R)
Skin cell
Larger
Smaller
= 0.2 millimeters (mm)= 0.008 inches or
8 1000 of an inch
125 hairs placed side by side take up 1 inch
125 hairs
Decreasing by factors of 10
Hair thickness
200 micrometers
Life is organized into cells
Prokaryotes – cells without nuclei: 4 billion years ago.Eukaryotes – cells with nuclei and other internal structures: less than 2 billion years ago.
Prokaryotes: No internal structures.They were the first cells thatlived on earth. Arose 4 billion years ago. Example: bacteria
Eukaryotes: Contain internal structures bounded by membranes, such as nucleus, mitochondrion. Less than 2 billion years ago. Examples: plants, animals, protozoa
We are outnumbered
• Eukaryotes are a tiny minority of all living things.
• However, because of their much larger size, their total collective mass is about equal to that of prokaryotes.
• We’ll learn more about this when we look at the living things inside you.
In complex organisms(multicellular organisms) cells are
organized together into tissues
Specialized proteins glue cells together
The Cells of the Human Body• Humans have about 200 different types of
cells.
–Within these cells there are about 20 different types of structures called organelles.
• All of these cell types are derived from a single fertilized egg cell. All cells have the same genetic material (genome).
How do cells become different?
• This is one of the most important current research questions.
• Difference between cells largely depends on which genes are turned on or off, and when.
• What controls this? This question is at the heart of modern genomic studies.
What Are the Important Chemical Components of Life?
There are 92 naturally-occurring elements
• From Hydrogen #1
• To Uranium #92
• An additional 26 elements have been artificially made in atom-smashers
What We are Made Of: Chemical Composition of the Human Body
Elements in the Human Body
Percent by Mass
Oxygen 65%
Carbon 18%
Hydrogen 10%
Nitrogen 3%
Calcium 1.5%
Phosphorus 1.2%
Potassium 0.2%
Sulfur 0.2%
Chlorine 0.2%
Sodium 0.1%
Magnesium 0.05%
Iron, Cobalt, Copper, Zinc, Iodine, Selenium, Fluorine
Verysmall
percentages,but all
important
“The big 6”
Only a relatively small number of elements make up organisms.
Atoms combine to form molecules
• The water molecule: 2 atoms of hydrogen (H) and 1 of oxygen (O), = H2O
• Molecules are held together by bonds, which are formed by the sharing of electrons.
• The molecules that compose living organisms are very large, containing thousands to tens of thousands of atoms.
The Important Chemical Components of Life
• Carbohydrates – sugars, starch, etc.
• Fats and oils
• Vitamins and minerals
Proteins
RNA
DNA
Proteins
• Proteins are the workhorses of the cell.
• Proteins are large molecules – thousands of atoms.
• Sizes are in the range of about 1 – 5.5 nm (nanometers, billionths of meters).
• They are made by stringingtogether smaller molecules called amino acids. Amino acids are
designated by 3-letter abbreviations.
PROTEINS
• A protein is a chain of amino acids linked in a definite sequence by chemical bonds.
• There are 20 amino acids commonly found in all organisms, plus one rare one.
• Each protein has a unique number and sequence of amino acids.
• This sequence is, in turn, determined by DNA.
All the amino acids have a common structure
R
R stands for one of the 20 different chemical groups that make each amino acid unique.
aminogroup
carboxylgroup
C = carbon. N = nitrogen. O = oxygen. H = hydrogen
The 21 amino acidsEssential – must be obtained in diet because they cannot be created from other compounds by the human body
Nonessential – can be made in the human body from other substances in the diet
Histidine AlanineIsoleucine Arginine*Leucine AsparagineLysine Aspartic acidMethionine Cysteine*Phenylalanine Glutamic acidThreonine Glutamine*Tryptophan GlycineValine Proline*
Selenocysteine* (very rare)Serine*Tyrosine*
* May be essential for certain ages or medical conditions
Amino acids have two ends that can join with other amino acids
These two groups can
bond together
This car is like an amino acid that can couple at both ends.
Just like railroad cars have two ends that can join with other cars.
Proteins are involved in every function of a cell
• Proteins vary greatly in size. • They range from about 100 amino acids to more than
1000 amino acids long.• Their functions include:
– Digestion– Energy production– Transporting nutrients– Antibodies– Channels, Pumps and Receptors– Photosynthesis– Enzymes for making and
recycling the molecules of life
After a protein is made, it folds into a unique 3-dimensional shape , dictated by its sequence of
amino acids.
Linear protein chain Folded-up protein in 3-D
The 3-D structures have 3 types of structural elements.
A 3-D View of a Protein – Human Serum Albumin – which is composed
entirely of helix
A 3-D animated view of this same protein
Static 2-D view
• Albumin occurs in the blood.• It has many functions, including carrying fats.
Let’s go to PDB and look at two more proteins:
• One spherical (an enzyme), which contains all 3 types of structure
• The other is myosin, one of the proteins of muscle, which is an elongated (fibrous) protein. It is entirely made of helix.
PFK, a human enzyme that metabolizes sugar
Human myosin, one of the muscle proteins
Proteins are related in families
• Just as families of organisms derive from a common ancestor, families of proteins result from divergent evolution of a single gene.
• Proteins in a family typically have similar three-dimensional structures, functions, and sequences.
• Computer programs are used to match proteins with others, sort them into families by sequences, and determine evolutionary histories.
The Cas-7 family of proteins
• These proteins help bacteria fight off virus attakcs – more later
Family tree for G
protein-coupled
receptors
An important family of signal-receiving proteins. At least 800 exist in humans.
• An example of a family of proteins:the cyclophilins, which help organize other proteins.
• Found in all cells of all organisms studied, in both prokaryotes and eukaryotes.
• Humans have a total of 16 cyclophilin proteins.
• Note similar 3-D shapes
An Important Biological Principle
Structure Determines
FunctionWhat a protein is capable of doing is entirely
determined by its 3-dimensional structure and which amino acids occupy each position.