The Gene
Author: Siddhartha Mukherjee
Missing Science of Heredity:
Pythagoras: Hereditary information carried in male semen. Spermism. Female provides nourishment. His devotees argued parents are like sides of triangle. Kid is hypotenuse.
Aristotle: Male semen has message, instructions or architecture. Female has the material.
Nobody for thousands of years could provide good alternate theories.
Charles Darwin: Went to South America for a survey for many years. Collected huge specimens of skeletons, plants, pelts, rocks, shells etc. He could see lot of variations in the same species in a particular island. It was as if each site had produced its own variant - a bar coded bird for each island.
What if all finches had arisen from a common ancestral finch ? What if current forms of animals are consequences of natural forces that had accumulated over millennia ?
Farmers breed and interbred cattle to produce natural variants. Reverse Darwinism. Deliberately created by humans.
When animals reproduce, they sometimes produce variants different from parents. Individuals within species are constantly competing for scarce resources. Variant better adapted for an environment is "naturally selected" . Survival of the Fittest. Freaks/Monsters are created, they survive, freaks become normals.
But Darwin could not explain Heredity. He came up with Pangenesis: Old idea. He mixed Aristotle and Pythagoras theories. Instructions from male and female met in embryo and blended together like colours.
Fleeming Jenkin disapproved Pangenesis. If it were true, then a variation might be diluted by interbreeding.
Gregor Mendel : Brno monk: Breeding peas to observe offsprings. Every trait was determined by an independent indivisible particle of information. Particles came in two variants or two alleles. Every plant inherited one copy from each parent, one from father, one from mother. When hybrid was created, both traits existed intact, although only one asserted its existence. In the next generation, this subsided trait can reappear.
Mendel's work was published but nobody cared for it for 40 years. Hugo De Vries coined the word "Mutants" for freaks of nature. He extended Mendel's work.
But nobody knew exactly what a gene was. Or its chemical composition.
Eugenics: In USA, sterilization of those who were mentally or physically not 100% fit started. Bell Vs Buck case most famous.
Thomas Morgan : Studied fruit flies. He observed mutants. Surprising pattern. Gene responsible for white eyes was almost linked to Y chromosome. So genes had to be physically linked to each other. Chromosome was a "string" along which certain genes were permanently strung.
If A was tightly linked to B and very loosely linked to C, then
A.B...................C
Russian Czars could be overthrown by communists as the Czar son had a genetic disorder of Hemophilia. Clotting was not happening properly. Czar queen had an affair with Rasputin who claimed he could treat her son.
Phenotype: Traits like physical beauty, looks, height.weight
Genotype : Combination of genes.
Phenotype = Genotype + environment + triggers + chance
Example: BRCA1 gene increases chance of breast cancer, but not all women carrying it develop cancer.
Chemical transformation of genes possible in bacteria. Pneumococcus responsible for Spanish Flu. Worst natural disaster in history killing 20 million people. Nonvirulent strain of it can become virulent by contact with dead bacteria. So gene is a chemical. X rays could change genes.
Nazism: Worst consequence of Genetics. Millions of Jews, Polish, Gypsies were gassed for "ethnic cleansing". Joseph Mengele tried cruel experiments on twins, trying to decode "nature vs nurture"
In Russia, opposite was happening. They tried giving "Shock therapy" to wheat to make it more resistant. Genetics became political agenda driving vehicles.
Chromatin: Genes resided here: Has proteins and nucleic acids. Proteins control fundamental chemical reactions to live like respiration. Proteins also form structural components of cell: like hair, nails, cartilage, hormones. Workhorses.
In the Sum of Parts, There are Only Parts:
Hemoglobin: Shaped like a 4 leaf clover. Each of these leaves clasps at center, an iron containing chemical called "Heme" that can bind and unbind Oxygen based on clasping and unclasping of these leaves. This helps in delivering Oxygen from lungs to heart and brain. Thus physical structure of molecule enables its chemical nature. Chemical nature enables its physiological function. Physiology ultimately permits its biological activity.
X-ray diffraction and Crystallography: 3 D structures are deduced by recording shadows of the 2D shapes illuminated in different positions. But in X-ray diffraction, shadows are actually scatters of X rays generated by a crystal. For liquids and solids, they crystallize and then apply this procedure.
Maurice Wilkins, a New Zealand biophysicist, wanted to use the above technique to get the structure of DNA. His college had another Rosalind Franklin, who worked on DNA as well. They did not get along well. She took good photos of "wet" DNA.
James Watson and Francis Crick: Most famous pair. Both wanted to solve the structure of DNA in Cambridge. They thought trying to solve structure of DNA using X-ray pictures was akin to guess the structure of piano listening to the sound it made. They somehow got the picture of "wet" DNA that Rosalind Franklin had taken, through Wilkins. They finally build the model. A-T and C-G paired and complemented each other.
Double Helix Structure: Each DNA strand is a long sequences of bases. A,T,G and C.
Genetic code occurs in triplets. 3 bases of DNA had to specify one amino acid in a protein. Example: ACT(Threonine), CAT(Histidine). Particular sequence of DNA: ACT-GGT-CCC builds an RNA chain ACU-GGU-CCC and RNA chains translated into chain of amino acids, ultimately leading to construction of protein.
Gene(Information) ---> Protein(Form)---> Function
DNA --> Copies itself to multiple RNA ---> Encodes amino acids in Proteins --> Function
DNA --> RNA --> Protein
Example: Sickle Cell: One change in the DNA triplet sequence from GAG to GTG. Causes change in one amino acid: Glutamate to Valine. Causes folding of hemoglobin chain, resulting in clumps instead of neat clasp-like structure. RBC then is shaped like "sickles" instead of flattened disks. This causes clots throughout the body interrupting blood flow and causes severe pain.
Another question: Why only RBC is affected because of genes. Every cell in the body inherits same genome copy. Why was there no hemoglobin in his eye or his skin ?
Pardee, Jacob and Monod published a paper known as 'Pajama' paper. Genes were not passive blueprints. Selective activation or repression of particular subsets of genes allows an individual cell to respond to its environments. Genome is an active blueprint, capable of deploying selected parts of its code at different times and in different circumstances.
Proteins act as regulatory sensors or master switches turning the genes on and off in a coordinate manner.
Gene Encodes a message --> Message builds Proteins --> Proteins regulate Genes --> Genes Encode a Message and so on.
Regulation, Replication and Recombination: 3 R's of Gene Physiology.
Regulation: Through transcription of DNA to RNA, depends on base pairing. This makes proteins which regulate genes.
Replication: DNA copies itself using its image. Genes make proteins that replicate genes, when a cell is divided into 2 cells or when a sperm or egg is generated.
Recombination: Ability to generate combinations of genes. During reproduction, paternal and maternal chromosomes hug each other and swap genetic information.
Another question: How genes make a whole organism grow back out of a single cell ? How hands comes out of limbs and not head? How eyes are in head and not in hands?
Maternal genes organize the early embryo into its main axes - head versus tail, front versus back, left versus right- using chemical gradients. Means proteins are deposited asymmetrically. Next, a series of genes initiate the division of embryo into its major structural parts, brain, spinal cored, skeleton, skin, guts and so forth. Finally, organ building genes authorize the construction of organs, parts and structures- limbs, fingers, eyes, kidneys, liver and lungs.
If you hammer 100 strips of wood atop each other, you get a wall. If you nail them side to side you get a deck. Else if you arrange them in a specific configuration, you get a boat. Genes operate in a similar manner. Individual genes specify individual functions but relationship among genes allows physiology.
Genes are like recipes of cake. It gives instruction about process. A cake is developmental consequence of sugar, butter and flour meeting each other in the right proportion, at right temperature and the right time. Human physiology is developmental consequence of certain genes intersecting with other genes in right sequence and in right space. Gene is one line in a recipe that specifies an organism. Human genome is the recipe that specifies a human.
The Dreams of Geneticists:
Paul Berg and David Jackson joined the entire genome of a virus called SV40 to a piece of DNA from a bacterial virus called Lambda bacteriophage and three genes from bacterium E.coli. These are called Recombinant DNA. "Genetic Chimera".
Boyer and Cohen stiched two pieces of genetic material together to form a single chimera which they introduced into bacterial cells. These cells were replicated in millions. "Cloning". Sheep was cloned first. Second instance of creation without sex, after Jesus Christ.
Genetics: Alphabets : A,G,C,T. Vocabulary : ACT, GAC. Syntax: Proteins with amino acid chains. Grammar: Regulation of genes turning them on and off.
Fred Sanger did gene sequencing using copying reaction of DNA polymerase.
Human Genome visualization:
This..........is..........the.(..)..s...truct..ure..of....geno..me
Words are genes. Dots are intragenic DNA. If the dots are between words like in geno..me, they are introns. Parantheses are regions of DNA that regulate genes.
Asilomar 2- Famous conference- Self imposed restrictions on gene cloning and sequencing.
Robert Swanson- Venture capitalist and Boyer started a company Genentech to synthesise Insulin in pancreatic tissue. This is a protein which regulates sugar in the body.They patented it to use it as a medicine.
Every medicinal drug tries to bind to its target protein and tries to switch them off or on.
Proper Study of Mankind is Man
Right of a child to be born free of genetic anomalies is a fundamental right declared a court. Abortion of fetus if found to have genetic disorders was made legal.
Huntington disease: Mutation is due to increase in number of repeats of amino acids to more than 40 in neurons and testicular issue. These pieces accumulate in tangled spools inside cells leading to their death and dysfunction.
Human Genome Project and TIGR- The Institute of Genomic Research both kind of worked on sequencing human genome.
Through the Looking Glass
Neanderthals co-existed with modern humans for about 5000 years.Overall diversity of human mitochondrial genome is less than that of chimpanzees. Humans are more homogeneous compared to them.
Mitochondria: Power House of the cell. Only mothers can pass it to child. Not father. This proves that we all have a single mother.
Sex determination: XX means female. XY means male. SRY gene is the single determinant of maleness. If it is off, then you cannot be a male. Its like the first step.
Some are genetically male. They have XY chromosome but anatomically they can be female because of some mutations.
There is no such single determinant gene like SRY to determine gay or straight. Multiple genes in multiple combinations result in sexual preferences.
Hunger Winter: Months of starvation in Netherlands by German troops caused permanent genetic changes that seeped into 2 generations. Offspring had obesity and other such issues. Hitler you asshole. Genetic memory was written into cellular memory.
Post Genome
Previvors : Those who anticipate some disease due to genetic mutations. Like those with BRCA1 gene have 70-80% chance of breast cancer.
Schizophrenia does not have such a single defining gene. It is a result of multiple factors.
ES cells or Embryonic Stem Cells: Can repair damaged cells of brain, blood,intestine,muscles,bone and skin. Can be isolated from embryo of an organism and grown in petri dishes in the lab.
Final Summary:
Missing Science of Heredity:
Pythagoras: Hereditary information carried in male semen. Spermism. Female provides nourishment. His devotees argued parents are like sides of triangle. Kid is hypotenuse.
Aristotle: Male semen has message, instructions or architecture. Female has the material.
Nobody for thousands of years could provide good alternate theories.
Charles Darwin: Went to South America for a survey for many years. Collected huge specimens of skeletons, plants, pelts, rocks, shells etc. He could see lot of variations in the same species in a particular island. It was as if each site had produced its own variant - a bar coded bird for each island.
What if all finches had arisen from a common ancestral finch ? What if current forms of animals are consequences of natural forces that had accumulated over millennia ?
Farmers breed and interbred cattle to produce natural variants. Reverse Darwinism. Deliberately created by humans.
When animals reproduce, they sometimes produce variants different from parents. Individuals within species are constantly competing for scarce resources. Variant better adapted for an environment is "naturally selected" . Survival of the Fittest. Freaks/Monsters are created, they survive, freaks become normals.
But Darwin could not explain Heredity. He came up with Pangenesis: Old idea. He mixed Aristotle and Pythagoras theories. Instructions from male and female met in embryo and blended together like colours.
Fleeming Jenkin disapproved Pangenesis. If it were true, then a variation might be diluted by interbreeding.
Gregor Mendel : Brno monk: Breeding peas to observe offsprings. Every trait was determined by an independent indivisible particle of information. Particles came in two variants or two alleles. Every plant inherited one copy from each parent, one from father, one from mother. When hybrid was created, both traits existed intact, although only one asserted its existence. In the next generation, this subsided trait can reappear.
Mendel's work was published but nobody cared for it for 40 years. Hugo De Vries coined the word "Mutants" for freaks of nature. He extended Mendel's work.
But nobody knew exactly what a gene was. Or its chemical composition.
Eugenics: In USA, sterilization of those who were mentally or physically not 100% fit started. Bell Vs Buck case most famous.
Thomas Morgan : Studied fruit flies. He observed mutants. Surprising pattern. Gene responsible for white eyes was almost linked to Y chromosome. So genes had to be physically linked to each other. Chromosome was a "string" along which certain genes were permanently strung.
If A was tightly linked to B and very loosely linked to C, then
A.B...................C
Russian Czars could be overthrown by communists as the Czar son had a genetic disorder of Hemophilia. Clotting was not happening properly. Czar queen had an affair with Rasputin who claimed he could treat her son.
Phenotype: Traits like physical beauty, looks, height.weight
Genotype : Combination of genes.
Phenotype = Genotype + environment + triggers + chance
Example: BRCA1 gene increases chance of breast cancer, but not all women carrying it develop cancer.
Chemical transformation of genes possible in bacteria. Pneumococcus responsible for Spanish Flu. Worst natural disaster in history killing 20 million people. Nonvirulent strain of it can become virulent by contact with dead bacteria. So gene is a chemical. X rays could change genes.
Nazism: Worst consequence of Genetics. Millions of Jews, Polish, Gypsies were gassed for "ethnic cleansing". Joseph Mengele tried cruel experiments on twins, trying to decode "nature vs nurture"
In Russia, opposite was happening. They tried giving "Shock therapy" to wheat to make it more resistant. Genetics became political agenda driving vehicles.
Chromatin: Genes resided here: Has proteins and nucleic acids. Proteins control fundamental chemical reactions to live like respiration. Proteins also form structural components of cell: like hair, nails, cartilage, hormones. Workhorses.
In the Sum of Parts, There are Only Parts:
Hemoglobin: Shaped like a 4 leaf clover. Each of these leaves clasps at center, an iron containing chemical called "Heme" that can bind and unbind Oxygen based on clasping and unclasping of these leaves. This helps in delivering Oxygen from lungs to heart and brain. Thus physical structure of molecule enables its chemical nature. Chemical nature enables its physiological function. Physiology ultimately permits its biological activity.
DNA: Deoxiribo Nucleic Acid : Called a stupid molecule. Carrier of genetic information. Removing DNA removed transformation of genes in bacteria.
X-ray diffraction and Crystallography: 3 D structures are deduced by recording shadows of the 2D shapes illuminated in different positions. But in X-ray diffraction, shadows are actually scatters of X rays generated by a crystal. For liquids and solids, they crystallize and then apply this procedure.
Maurice Wilkins, a New Zealand biophysicist, wanted to use the above technique to get the structure of DNA. His college had another Rosalind Franklin, who worked on DNA as well. They did not get along well. She took good photos of "wet" DNA.
James Watson and Francis Crick: Most famous pair. Both wanted to solve the structure of DNA in Cambridge. They thought trying to solve structure of DNA using X-ray pictures was akin to guess the structure of piano listening to the sound it made. They somehow got the picture of "wet" DNA that Rosalind Franklin had taken, through Wilkins. They finally build the model. A-T and C-G paired and complemented each other.
Double Helix Structure: Each DNA strand is a long sequences of bases. A,T,G and C.
Genetic code occurs in triplets. 3 bases of DNA had to specify one amino acid in a protein. Example: ACT(Threonine), CAT(Histidine). Particular sequence of DNA: ACT-GGT-CCC builds an RNA chain ACU-GGU-CCC and RNA chains translated into chain of amino acids, ultimately leading to construction of protein.
Gene(Information) ---> Protein(Form)---> Function
DNA --> Copies itself to multiple RNA ---> Encodes amino acids in Proteins --> Function
DNA --> RNA --> Protein
Example: Sickle Cell: One change in the DNA triplet sequence from GAG to GTG. Causes change in one amino acid: Glutamate to Valine. Causes folding of hemoglobin chain, resulting in clumps instead of neat clasp-like structure. RBC then is shaped like "sickles" instead of flattened disks. This causes clots throughout the body interrupting blood flow and causes severe pain.
Another question: Why only RBC is affected because of genes. Every cell in the body inherits same genome copy. Why was there no hemoglobin in his eye or his skin ?
Pardee, Jacob and Monod published a paper known as 'Pajama' paper. Genes were not passive blueprints. Selective activation or repression of particular subsets of genes allows an individual cell to respond to its environments. Genome is an active blueprint, capable of deploying selected parts of its code at different times and in different circumstances.
Proteins act as regulatory sensors or master switches turning the genes on and off in a coordinate manner.
Gene Encodes a message --> Message builds Proteins --> Proteins regulate Genes --> Genes Encode a Message and so on.
Regulation, Replication and Recombination: 3 R's of Gene Physiology.
Regulation: Through transcription of DNA to RNA, depends on base pairing. This makes proteins which regulate genes.
Replication: DNA copies itself using its image. Genes make proteins that replicate genes, when a cell is divided into 2 cells or when a sperm or egg is generated.
Recombination: Ability to generate combinations of genes. During reproduction, paternal and maternal chromosomes hug each other and swap genetic information.
Another question: How genes make a whole organism grow back out of a single cell ? How hands comes out of limbs and not head? How eyes are in head and not in hands?
Maternal genes organize the early embryo into its main axes - head versus tail, front versus back, left versus right- using chemical gradients. Means proteins are deposited asymmetrically. Next, a series of genes initiate the division of embryo into its major structural parts, brain, spinal cored, skeleton, skin, guts and so forth. Finally, organ building genes authorize the construction of organs, parts and structures- limbs, fingers, eyes, kidneys, liver and lungs.
If you hammer 100 strips of wood atop each other, you get a wall. If you nail them side to side you get a deck. Else if you arrange them in a specific configuration, you get a boat. Genes operate in a similar manner. Individual genes specify individual functions but relationship among genes allows physiology.
Genes are like recipes of cake. It gives instruction about process. A cake is developmental consequence of sugar, butter and flour meeting each other in the right proportion, at right temperature and the right time. Human physiology is developmental consequence of certain genes intersecting with other genes in right sequence and in right space. Gene is one line in a recipe that specifies an organism. Human genome is the recipe that specifies a human.
The Dreams of Geneticists:
Paul Berg and David Jackson joined the entire genome of a virus called SV40 to a piece of DNA from a bacterial virus called Lambda bacteriophage and three genes from bacterium E.coli. These are called Recombinant DNA. "Genetic Chimera".
Boyer and Cohen stiched two pieces of genetic material together to form a single chimera which they introduced into bacterial cells. These cells were replicated in millions. "Cloning". Sheep was cloned first. Second instance of creation without sex, after Jesus Christ.
Genetics: Alphabets : A,G,C,T. Vocabulary : ACT, GAC. Syntax: Proteins with amino acid chains. Grammar: Regulation of genes turning them on and off.
Fred Sanger did gene sequencing using copying reaction of DNA polymerase.
Human Genome visualization:
This..........is..........the.(..)..s...truct..ure..of....geno..me
Words are genes. Dots are intragenic DNA. If the dots are between words like in geno..me, they are introns. Parantheses are regions of DNA that regulate genes.
Asilomar 2- Famous conference- Self imposed restrictions on gene cloning and sequencing.
Robert Swanson- Venture capitalist and Boyer started a company Genentech to synthesise Insulin in pancreatic tissue. This is a protein which regulates sugar in the body.They patented it to use it as a medicine.
Every medicinal drug tries to bind to its target protein and tries to switch them off or on.
Proper Study of Mankind is Man
Right of a child to be born free of genetic anomalies is a fundamental right declared a court. Abortion of fetus if found to have genetic disorders was made legal.
Huntington disease: Mutation is due to increase in number of repeats of amino acids to more than 40 in neurons and testicular issue. These pieces accumulate in tangled spools inside cells leading to their death and dysfunction.
Human Genome Project and TIGR- The Institute of Genomic Research both kind of worked on sequencing human genome.
Through the Looking Glass
Neanderthals co-existed with modern humans for about 5000 years.Overall diversity of human mitochondrial genome is less than that of chimpanzees. Humans are more homogeneous compared to them.
Mitochondria: Power House of the cell. Only mothers can pass it to child. Not father. This proves that we all have a single mother.
Sex determination: XX means female. XY means male. SRY gene is the single determinant of maleness. If it is off, then you cannot be a male. Its like the first step.
Some are genetically male. They have XY chromosome but anatomically they can be female because of some mutations.
There is no such single determinant gene like SRY to determine gay or straight. Multiple genes in multiple combinations result in sexual preferences.
Hunger Winter: Months of starvation in Netherlands by German troops caused permanent genetic changes that seeped into 2 generations. Offspring had obesity and other such issues. Hitler you asshole. Genetic memory was written into cellular memory.
Post Genome
Previvors : Those who anticipate some disease due to genetic mutations. Like those with BRCA1 gene have 70-80% chance of breast cancer.
Schizophrenia does not have such a single defining gene. It is a result of multiple factors.
ES cells or Embryonic Stem Cells: Can repair damaged cells of brain, blood,intestine,muscles,bone and skin. Can be isolated from embryo of an organism and grown in petri dishes in the lab.
Final Summary:
- Gene is the basic unit of hereditary information.
- Genetic code is universal.
- Genes influence form, function and fate but these do not occur in 1:1 manner.
- Variation in genes contributes to variation in features, forms and behaviours.
- Nature vs nurture debate is nonsense in absolutes or abstracts.
- Mutants are natural.
- Many human diseases are genetic, and are due to mismatch in genome and its environment.
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