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.