How natural selection took over immunology

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• Read: Clonal selection theory.

• If an organism is infected, it produces antibodies.

• The body has antibodies for even artificial synthestic novel foreign bodies when injected.

• Antigens + Antibody results in a precipitation reaction.

• Electrophorosis of Serum Globulin, Sanger Sequencing.

• Ultra-centrifugation of antibody precipitation to differentiate IGG and IGM.

• Criticisms of the Pauling approach where the Globulin changes conformation and wraps around the threat fails to explain the exponential growth observed in the concentration of antibodies over time.

• Skin grafting was a hot field after war. The rejection of foreign tissue was well known. If the same person is given the same tissue a second time it rejects is faster. This indicated an immuological response.

• If in embroyonic life, foreign cells are introduced, then the body develops no immunological response to it. This is not entirely true, as only some particular type of tissues work this way.

• Self-on-self-discrimination: the immune system discriminates between the tissues of its own body vs foreign objects.

• The natural selection theory of Antibody Formation by Jesse.

• Genes and Antibodies by Joshua Lederberg.

• PAMP: Pathogen Associated Molecular Patterns.

• Recommendation for immunology Textbook: Janeway´s Immunobiology.

Drosophilia and Beyond: Experimental Systems in Genetics

• The designation of the “model organis1m” was given to a set of organisms by the Human Genome Project in 1990.
• How did the fly become such a dominant model organism in research?
• Science is produced locally, but it transmits globally.
• Universality: an idea of the epistemic validity of Science
• Locality:c science is influences by its local conditions of production
• Globally: the circulation of scientific knowledge, materials, and practices from one location to other.
• Thomas Hunt Morgan, American was responsible for coming up with Drosophilia model systems.
• Morgan get the Nobel Prize for “The Mechanisms of Mendelian Heridity”.
• He inbred flies in the lab in a bio-reactor to amplify rare mutations.
• The first mutant he discovered was controlling the eye color of the fly.
• He also found that mutations co-occur. So you can put mutations into discrete groups based on co-occurance.
• Chromosomes can cross over which results in recombination of genes.
• Recombination rates can be used as a measure of proximity. From this methotend to kill you, its d they were able to create a linear photo-map of the genes. This gets the PI a nobel prize.
• This also cements the Chromosome-gene theory for genetics.
• Gene is the unit of Structure, Function, Recombination, and Mutation.
• Morgan runs a tight ship of the Boss and the Bois.
• Chromosomes are proteins + DNA. Its Nucleoproteins.
• H.J. muller invents the Balanced Lethal Assay. He was able to show that their is a linear relationship between X-ray dosage and the amount of mutations. He got the nobel prize for this.

Mammalian Genetics

• “Got a weird mouse? Kill it and ship it to Harvard!”

• The process and hence the research is much slower.

• Seawell Wright works extensively on Gunnie pigs.

• Because mutations in development tend to kill you, they are difficult to detect.

• Mammal and maize geneticists were interested in variable phenotypes.

• The variability of phenotypes and their mixtures can be explained by bringing time into picture. It is the temporal dependece of certain genes.

Conclusions

• The locus of univerality in Biology is the genetic code. Nothing else is universal in any way. Organisms evolve over time in complex ways to produce very distinct organismic systems.

Genes in Action: The history of Development and genetics

• Thomas Hunt Morgan was trained as an embryologist (a developmental biologist) but didnt adress problems from this field, ever!

• Wilhelm Roux develops developmental mechanics and really likes experiments. “There are particles that determine the type of cell that develops.”

• Where (and what) is the determinant of Development?

• Jacques Loeb advocates the Reductionist Approach. He also thinks that Genes as Protein and Gene actions are enzyme Actions.

• Richard Goldschmidth (color blind Gypsy moth guy) was trained with the German Morphological tradition: which is highly descriptive biology.

• Temporal Regulation: how much you produce something and when you produce something are both crucial factors.

• Linking Genes and Development can be attributed to Viktor Hamburger and Walter Landauer who were German exiles.

• The dorsal fold plays an important role during embryonic development (Spealman and Mar…) It acts as an organiser of the cell.

• Dead cells in the dorsal fold (in the organiser) also work. Hence, it was induced that the organiser is actually a chemical signal released by the dorsal fold area.

• Development is seen as a phenomena that operates around t a network of chemical inducers that are responsible for producing different kinds of tissues. “A cascade of inducers.”

• Non-competent cells are not ready to receive a signal. Hence, time becomes important. It is also noteworthy that early developmental biologists thought that genes were not responsible for these “particles” (inducers), are purely chemical in nature. The question of the first inducer is still open.

• Embronic development starts with making a normal table of development for a particular system.

• Homeotic Mutant: has a full body part where it was not supposed to be.

• Waddington´s Branching track Model for Aristapedia (which is a fly).

• Waddington is able to map variable pheontypes using the branch track model.

• Waddington´s cannalization theory with different developmental channels. Remember the dynamical attractors in ecology paper (PNAS).

• George Beadle, Ed Tatum : the birth of Biochemical Genetics. The use Neurospra (bread mould).

• They come up with the one-gene one-enzyme model. This creates biomedical genetics. You can now say: “This gene is responsible for this broken metabolic process.”

  flowchart LR Gene -."and".- Nutrients --> Proteins Proteins --Histogenesis --> Cells Cells --Morphogenesis-->Organisms

• “Never trust a Biologist about their histories.”

• Bacteria-Phage Radioactive tagging experiment that determines that DNA is being transfered a sthe genetic code.

Better than Darwin: The Rise of the Evolutionary Synthesis

• Population Genetics: focus on population measure and its statistics. founded by J.B.S Haldane, Seawall Wright, and Fisher.

• Hardy-Weinberg Principle $$ p^2 + 2pq + q^2 = 1 $$

  • $p^2$ is the frequency of AA
  • $2pq$ is the frequency of Aa
  • $q^2$ is the frequency of aa, A, a are alleales.

• There are forces than increase variability and those that decrease variability.

• Sampling can drastically change the genetic makeup of the population, for example, 1 single sperm is sampled from millions during reproduction.

• A fitness landscape that can be topologically represented superimposes an infinite hypercube of the genotype network. All the organisms navigate this changing topological landscape.

• Peak Shift Problem

• Species and Ring Species: different clusters of the birds look like a neighbouring cluster but clusters far away look very different. The clusters are loosely isolated geographically.

  graph LR Geographic-Isolation-->Genetic-Isolation-->Reproductive-Isolation-->Speciation

• The Great Evolutionary Constriction was the ruling out of certain ideas about Evolutionary Synthesis but no concensus was obtained.

• Read about Homozygous or heterozygous.

• The classical/Balance Controversy: which lead to global nuclear policy.

  • Genetic Variation: a wild sample is more Homozygous or Heterozygous?
  • The Action of Selection: Is natural selection most often purifying or balancing?
  • Radiation
  • Eugenics

• Hybrid Vigour: 1 single sickle cell alleale gives resistance to malaria.

• Bruce Wallace and King did experiments with D flies, where you expose low power chronic vs high power chronic radiation. The adaptive value (or number of offsprings) was 0.92, 0.95 and 1.04 respectively.

• You can’t reproduce this experiment as only the exposure can be reproduced not the random mutations.

• Radiation exposure and population fitnes was very difficult to quantify.

• Electrophorosis: seperation of molecules based on size and charge. Lewontin and Hubby (1966) used this method to seperate the genetic matter. This allowed for a quantitative measure of the variability in species.

• The average individual in a population was heterozygous for 8% to 15%, the avaerage being 12%.

• Electrophorosis becomes a trend. Because it was fast.

• Neutal theory: most mutations are neutral and don’t affect the organism’s fitness.

• Sequence revolution: a lot of variability in the clones.

• Neutral Theory is the new Null Model. Assume neutrality unil disproven by a statistical test.

• National Museum of Creationism in Connecticut - Sex, Drugs, and Rock and roll is the path to sin.

Hopeful Monsters: EvoDevo and the Revival of Richard Goldschmidt’s Heresies

• Richard Goldschmidt, German, was part of the Kieser Wilhelm Institute which is today’s max Plank institutes. He then moves to Berkely.

• Sturtevant discovered that if genes are close to each other (neighbours) they affect each other. It is called the Position Effect.

• Goldschmidt’s presents the Genetic Hierarchy which states that the genes can be grouped from single gene, to gene clusters, to whole chromosoms. The different cardinal groups can transporf and transform in an affine manner.

• In his book, The Material Basis of Evolution (1940), he introduces the concept of Gradual vs Saltation rates of evolution. Which morphs into Microevolution and Macroevolution.

• There are Systemaic mutations, which are Chromosal emphasis. And there are Regulatory Mutations which have a Developmental emphasis.

• Homeotic Mutant:

• “What good is one hopeful monster?” : Seawall Wright tackles this problem. He proposes that the major mutations are eventually finetuned while they wait some time to be expressed.

• Goldschmidt could never get published in the journal Genetics. Because he didi little experimentation and wild theorizing.

• His work never took off in his life but got really popular in the 1980s becuas ehis work was resurrected by Steven Jay Gould.

• Gould says “Punctuated Equilibrium is not a theory of macro mutation. It is not a Theo” #TODO

• The Evo-Devo scientists understand Hox genes. The real break arrives with The Ubx Revival. They try an experiment where they modify a single gene which transforms a fly into a thing with many legs.

• The Uses of Heresy: An Introduction to Richard Goldschmidt’s The Material Basis of Evolution by Stephen Jay Gould: he produces a usable history.

  Reading Notes - Assignment

  Visual Summary of the findings from the Abstract

  flowchart LR Toll-Protein* --activates--> NF-KB NF-KB --expresses--> Inflamatory-Cytokines NF-KB --expresses--> Co-stimulatory-molecules subgraph Inflamatory-Cytokines IL-1 IL-6 IL-8 end subgraph Co-stimulatory-molecules B7.1 end

  Some Interesting Takeaways from the first reading

  • “It thus appears that the immune-response system mediated by Toll represents an ancient host defence mechanism” (Medzhitov et al., 1997, p. 394)
  • “Alignment of the sequences of the human and Drosophila Toll proteins shows that there is homology over the entire length of the protein chains” (Medzhitov et al., 1997, p. 394)
  • “The hToll gene is expressed most strongly in spleen and PBL (Fig. 3); its expression in other tissues may be due to the presence of macrophages and dendritic cells, in which it could act as an early-warning system for infection.” (Medzhitov et al., 1997, p. 394) [in mice and human cell lines]
  • “Alternatively, hToll may be widely expressed because hToll signals through the conserved NF-kB pathway (see below) and NFkB is a ubiquitous transcription factor.” (Medzhitov et al., 1997, p. 394)
  • A homologous immune response system based on the Toll signalling domain is used in plants, insects and vertebrates. In mammals, Toll induces signals required for the activation of both an innate and an adaptive immune response.

  Assumptions/Educated Guesses

  • Toll Protein extends through the membrane of the cell and has a intra and an extra cellular domain.

  • mRNA for Toll proteins was only found in certain tissues in

  How we know genes are made of DNA? | Lars Jansen

• Data is not knowledge.

  

• Indirect evidene often proves direct evedence.

• Correlation (requires observation) is different than Causation (requires manipulation).

• What is the physical nature of the gene?

  Erwin Schrodinger wrote What is life? where he described The gene is an aperiodic crystal. He was wrong but he put a physical description of the gene which was rather rare.

• Where does the gene reside?

  Walter Flemming discovers chromosomes. Then we have The chromosome theory of heredity by Theodor Boveri and Walter Sutton.

  The white gene was on the X-chromosome on the Drosophila — it was the first genes to be mapped.

  The Fly Room (movie)

• What are the genes made of?

  The idea that information can be encoded only came after during the 19th century.

  Read about Frederick Griffith’s discovery in 1928 :

• It is easy to prove something is there but practically impossible to prove something is not there.

• The introduction of Phycisists in Biology

  • Max Delbruck: Introduction of a reductionist and quantitative approach to biology
  • The Hershey - Chase experiment brought the use of radioactive probing in Biology.
  • As any hypothesis becomes more acceptable in the scientific community, the bar for the evidence required to prove it comes down lower.

• The Meselson - Stahl experiment a.k.a the most beautiful experiment in biology.

  • Read the PNAS paper.

  • Liquid Hold Recovery: Cells recover after damage if they are held vs if they are allowed to grow in plate or with light.

• What do genes actually do? Pleiotropic in action (i.e. Having multiple primary effects)

• The Adaptor Hypothesis was proposed by Francis Crick to explain the flow of information from DNA to Proteins.

• Don’t let inconcistencies destroy an emerging hypothesis.

• Transfer RNA was the adapter protein: Sometimes the control becomes the experiment.

• 20 qmino acids and 4 bases.

• Read: General Nature of the Genetic Code for Proteins — Nature declared this as the best paper of the 19th century.

• Understand what a “wild type” actually is.

• “Frame Shift Mutation” : demonstrated the existence of a non-overlapping triple base genetic code.

• The discovery of gene regulation: Most proteins that are incoded are regulators of other genes.

Type of Experiments

• Sufficiency experiments (most Genetic experiments fall in this category)
• Necessatity experiments