Why oh why did I not give a dissected rat’s ass about biology in high school?

This was an incredible book. Big thanks to Nick Drayson for the recommendation. I had Mukherjee’s other book – the Pulitzer-prize-winning A Biography of Cancer – on the curriculum, but I think The Gene made more sense to go through first as a broader history.

Mukherjee is a cancer physician and researcher, and unlike other biologists I tried to read recently (cough George Church cough) he is a joy to read. Here’s an example of his brilliant writing:

​The woman looked at my father warily. He had already stepped past the threshold and climbed onto the raised veranda, a few feet from the kitchen. “Does Bibhuti’s family still live here?” The questions were launched without any formal introduction. I noted a deliberate change in his accent-the softened hiss of the consonants in his words, the dental chh of West Bengali softening into the sibilant ss of the East. In Calcutta, I knew, every accent is a surgical probe. Bengalis send out their vowels and consonants like survey drones-to test the identities of their listeners, to sniff out their sympathies, to confirm their allegiances.

“No, I’m his brother’s daughter-in-law,” the woman said. “We have lived here since Bibhuti’s son died.”

It is difficult to describe what happened next-except to say that it is a moment that occurs uniquely in the histories of refugees. A tiny bolt of understanding passed between them. The woman recognized my father not the actual man, whom she had never met, but the form of the man: a boy returning home. In Calcutta-in Berlin, Peshawar, Delhi, Dhaka men like this seem to turn up every day, appearing out of nowhere off the streets and walking unannounced into houses, stepping casually over thresholds into their past. Her manner warmed visibly. “Were you the family that lived here once?

I will read all the science books you can send me that have such great writing!

Mukherjee takes us through the history of the field of genetics from The Ancients’ beliefs about heredity all the way to today’s CRISPR-driven ethical questions and geopolitical impact. It’s not just the story of understanding how our bodies are built & maintained, it’s also about how our society has clumsily wrestled with this new power.

My notes follow – enjoy!

Part I: The “Missing Science of Heredity” (1865-1935)

Spermism, preformation, and taxonomies

• Pythagoras & co had a theory that heredity was carried exclusively in male semen (“spermism“). Aristotle showed that women also transferred traits
• Up until the 18th century belief in preformation, that organisms develop from miniature versions of themselves

• Late 18th century natural history was dominated by vicras, parsons, monks, who cultivated plants, animal specimens. Did a lot of taxonomy of species but not allowed to question the origins and mechanics too much.

Let’s bread some peas for a few decades:

• Gregor Johann Mendel (1822-1884) in Silesia (Poland today). Priest in training more drawn to studying natural sciences
• Taught by Christian Doppler, who showed the Doppler effect by packing a train with trumpet players and having people at the train station notice the change in pitch as the train approached and left!
• Doppler’s empirical approach inspired Mendel. Mendel’s core question: How does a single organism transmit information to its offspring over a single generation?
• Through breeding pea plants over decades, discovered the concept of alleles, dominant and recessive traits. Planted 28k plants, 40k flowers, 400k seeds. Working by himself, and was barely cited
• His experiments implied the passage of a unit of information between the parent & offspring, later called a gene
• In his experiments, each gene behaved like an independent entity. Each characteristic inherited independently, and all combinations of traits were possible
• Mendel forgotten then rediscovered in early 1900s

Let’s go sailing:

• Darwin 1809-1882. 1831, The Beagle leaves. Darwin’s core question: How do organisms transmute (change) information about their features over thousands of generations?
• Malthus paper on human population in constant struggle with its resource pool was the click for Darwin, seeing death as nature’s culler – survival of the fittest
• Darwin didn’t understand how new species come about (when organisms can no longer reproduce viably with eachother, typically due to physical barrier between them)
• Alfred Russel Wallace coming onto the same theory and pushed Darwin to publish his work (competition spurring publications once again… lots of that in the CRISPR story)

The birth of “genetics”:

• In Cambridge, group of students formed around English biologist William Bateson, coined the word Genetics in 1905 (derived from the Greek genno – “to give birth”)
• Bateson nicknamed “Mendel’s bulldog” as he was a very fervent supporter and fighting to give him credit
• 1901 “gene” coined by botanist Wilhelm Johannsen, 1 century after “atom”
• Bateson’s prescience:
  • “One thing is certain: mankind will begin to interfere; perhaps not in England, but in some country more ready to break with the past and eager for “national efficiency”…”
  • “When power is discovered, man always turns to it”

Eugenics:

• 1883, Darwin’s cousin Francis Galton published a book which laid out a strategic plan for improvement of the human race
• Started studying human traits with huge surveys, understanding eg height across generations (his biggest contribution was the regression to the mean phenomenon)
• Along with HG Wells and others, formed the eugenics movement
• First International Conference on Eugenics in 1912, widely attended. Charles Davenport (Harvard-trained zoologist) leading the movement in the US

• “Feeblemindedness” defined in 1924 in the US (three kinds: idiot, moron, imbecile). Initially feebleminded women sent to Virginia State Colony for confinement
• Buck vs Bell Supreme court case, in 1927 ruled 8-1 that it’s better to cut Fallopian tubes of feebleminded women than wait to prosecute their offspring for crimes…
• 1920s “Better Babies Contests” evaluating the fittest babies

Part II: Deciphering the Mechanism of Inheritance (1930-1970)

The gene as an abstraction:

• “It is a testament to the ability of scientists to accept abstractions as truths that fifty years after the publication of Mendel’s paper – from 1865 to 1915 – biologists knew genes only through the properties they produced: genes specified traits; genes could become mutated and thereby specify alternative traits; and genes tended to be chemically or physically linked to each other. […] No one had seen a gene in action or knew its material essence.”
• It was only visible in a statistical sense (even though genetics was used to justify huge social change). We didn’t know what it was made of, how it accomplished its function, where it resided within the cell

Morgan’s Fly Room:

• Thomas Morgan, professor of zoology at Columbia. Approached these questions by studying and breeding fruit flies, maggots, in 1910s
• Discovered that fruit fly genes didn’t always behave independently (as in Mendel experiments): some genes acted as if they were “linked” with each other
• “In flies the gene for sable color was never (or rarely) inherited independently from the gene for miniature wings because they were both carried on the same chromosome”
• Key discoveries
  1. Genes are linked together, located on chromosomes. Links the fields of cell biology and genetics
  2. “Crossing over”. Occasionally a gene could unlink itself from its partner genes and swap places from the paternal chromosome to the maternal chromosome
  3. Tightness of genetic linkage. Some genes were so tightly linked that they never crossed over
• 1905-1925, the Fly Room at Columbia was the epicenter of genetics, lots of Nobels

Dobzhansky:

• Theodosius Dobzhansky, Ukrainian biologist who trained with Morgan
• Mendel model was: “a gene determines a physical feature”
• Dobzhansky model: “a genotype + an environment + chance + a trigger determines a phenotype”
  • Environment: showed through wild fly experiments (“Galapagos in a carton”)
  • Chance: showed mutations
  • Trigger: will the gene get expressed or not
• Also showed that geographic isolation leads to genetic isolation, and to eventual reproductive isolation (formation of new species)
• Issued strident moral warnings against oversimplication of the logic of genetics (trying to select phenotypes) in eugenics and then rise of Nazi Germany

Deducting the physical form of genes:

• Transformation: “horizontal” exchange of genes from one organism to another, not “vertically” between a parent and child, but between two strangers
  • Almost never occurs in mammals, but in early 1920s was discovered by Frederick Griffith in pneumococcus bacteria following the Spanish flu
• Experiments that launched the molecular biology revolution.
  • Injecting heat-killed bacteria debris into mice showed that the harmless bacteria could transform into virulent form
• Griffith finally published in 1928. Effectively showed transmutation, and that the gene was chemical
  • Hermann Muller, confirmed showing that radiation increased the mutation rate in flies

Nazi euthanasia:

• “Nazism nothing more than applied biology”.
  • By 1934, nearly 5000 adults were being sterilised each month
  • Then broad euthanasia program, “defective” children under 3, then adolescents, juvenile delinquents
• In the Soviet Union, Trofim Lysenko pushed “shock therapy” theory that all life forms could be “reeducated”.
  • Fit well with the regime “anyone is everyone” ethos.
  • Outlawed any Mandelian or Darwinian thinking.
• Did Nazi geneticists make any real contributions to the science of genetics? “Amid the voluminous chaff, two contributions stand out:”
  1. twin studies
  2. exodus of scientists, many physicists & chemists moving to biology

Find my DNA:

• The biological structure where genes reside is called chromatin. It’s composed of proteins and nucleic acids
• Proteins are the workhorses of the biological world. “Proteins coax and control these fundamental chemical reactions in the cell – speeding some and slowing others, pacing the reactions just enough to be compatible with living.“
• Oswald Avery paper in 1944 showed that genetic information was in one of the two nucleic acids – DNA. Was refused the Nobel because influential Swedish chemist Hammarsten refused to believe that DNA would carry genetic information…

Discovering the structure of DNA:

• Biochemistry studies the workings of: Physical structure -> chemical nature -> physiological function -> biological function
  • eg hemoglobin, which carries oxygen in blood, and binds to oxygen when exposed to high levels, releases it when in an area with low levels. Enables blood to carry 70x more oxygen than what could be dissolved in liquid blood alone
• Wilkins pet project at King’s was solving the 3D nature of DNA. Using crystallography and X-ray diffraction.
  • Transform a molecule to a crystal, and its atoms are instantly locked into position. Shine X-ray at it and read the silhouettes of atoms
  • Rosalind Franklin joined him in 54. Relationship soured. She adjusted the humidity of the chamber to be able to take clearer X-ray photographs (DNA had different form in presence of H2O)
• Watson & Crick’s most intuitive scientific leap was to try to build a simple model that would fit the data & chemical properties
• Watson & Crick paper ended with: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for genetic material”
  • Each strand is used to generate a copy of itself

Genes encode RNA which build proteins

• 1941, Beadle and Tatum at Stanford studying the link between “gene for redness” and “red eyes” in flies. “Every mutant, they noted, was missing the single metabolic function, corresponding to the activity of a single protein enzyme.” So the gene must specify the information to make the normal enzyme.
• How did the gene encode the information to build a protein? RNA, a “facsimile” of the gene which was used as a working source for translation into a protein
• Sickle-cell disease – one DNA triplet goes from GAG to GTG, glutamate amino acid switched to valine, alters the folding of the hemoglobin chain.

Gene-regulation:

• Jacques Monod in the 40s in Paris (under occupation) studied E.coli. Showed that the growth rate changed when switching from glucose to lactose feeding
• Discovered gene regulation: how can an organism have a fixed set of genes, yet respond so acutely to changes in the environment?
  1. Rate of RNA messages production is variable, influenced by enzymes
  2. This production is coordinated, “functional circuit of genes turned on/off” called an operon
  3. Every gene has DNA sequences appended to it that act like recognition tags (not just info about a gene, but also about when and where to make the protein)

Sources of mutations

1. DNA is damaged by chemicals or X-rays, or DNA replication enzyme makes a spontaneous error
2. Genetic information can be swapped between chromosomes, eg DNA from maternal chromosome can exchange position with DNA from paternal chromosome, potentially generating a gene hybrid. “Jumping genes” discovered by McClintock

Anatomists vs physiologists

• Anatomists: “how things are”, nature of materials, parts. Mendel, Morgan, Watson, Crick
• Physiologist: how things work, how these structures enable functions. This was the focus from the late 50s to late 70s. Led to understanding gene regulation, recombination, mutations

From genes to genesis:

• The gene solves one problem – the transmission of heredity – but creates another: the development of organisms.
• This was figured out in reverse: first how genes specify macroscopic anatomical features (limbs, organs, structures), then how an organism determines where these structures should be placed
• Ed Lewis at Caltech studying fly embryos (embryo -> first segment in only 700mins)
  1. Axis determination (1986-90 we discovered chemicals that signal “headness” and “tailness”)
  2. Segment formation
  3. Organ building
• Which genes control these events? How many are they? Do they cooperate or are they working independently of each other?

• How do cells arising in an embryo know what to become? Brenner, Sulston, Horvitz mapping the lineage of all 959 adult cells of worms (we have 37 trillion each)
• Cells have genes that orchestrate their own death. In human cells the activation of BCL2 results in a cell in which the death cascade is blocked, creating a cell that is pathologically unable to die: cancer.
• Cell identity constructed from “intrinsic” input from genes and “extrinsic” cell-cell interactions

How can units of heredity generate the bewildering complexity of organisms?

• “A single master-regulatory gene might encode a protein with rather limited function: an on-off switch for twelve other target genes, say. But suppose the activity of the switch depends on the concentration of the protein, and the protein can be layered in gradient across the body of an organism“
• Dawkins metaphor: some genes behave like blueprints, some like recipes

Part III: Sequencing and Cloning of Genes (1970-2001)

• Paul Berg created the first “recombinant” DNA (made from different organisms). From his Nobel page:
  • “DNA carries organisms’ genomes and also determines their vital processes. The ability to artificially manipulate DNA opens the way to creating organisms with new characteristics. In conjunction with his studies of the tumor virus SV40, in 1972, Paul Berg succeeded in inserting DNA from a bacterium into the virus’ DNA. He thereby created the first DNA molecule made of parts from different organisms. This type of molecule became known as “hybrid DNA” or “recombinant DNA”. Among other things, Paul Berg’s method opened the way to creating bacteria that produce substances used in medicines.”
• Boyer & Cohen showed that genetic material could be transferred between species
  • “They snipped a piece of Staphylococcus plasmid (Staphylococcus is the bacteria responsible for staph infections), spliced it with one of the many E. coli plasmids, and inserted the whole in E. coli. The DNA from Staphylococcus, a different species of bacteria, was successfully propagated in E. coli. An even greater triumph of interspecies cloning was the insertion into E. coli of genes taken from the South African clawed frog.”
• First DNA-based genome to be sequence was phi X 174 virus by Fred Sanger. From his Nobel page:
  • “In 1977, Frederick Sanger developed a method based on using small amounts of what are known as dideoxynucleotides. These can be inserted into the DNA chain, but at a certain nucleotide they stop growth of the chain so that fragments of different lengths are created. After undergoing what is known as electrophoresis, the nucleotide sequences in a DNA sample can be identified.”

Regulation

• Berg’s initial experiments were thorny at the time because SV40 was known to cause tumor in hamsters, and was being inserted in E.Coli which is known to live in the human intestine
• Asilomar conference organised by Berg in 1975. Scientists self-issued a moratorium use or recombinant DNA technology and placing research into public domain for visibility.

Genentech: the birth of biotech

• Cohen & Boyer irritated by Asilomar, wanted to realise the promise of creating “biological factories” for drugs or chemicals.
• 28 year old Rob Swanson reached out to Boyer and together they started Genentech (“genetic engineering technology). 100k seed from Kleiner
• They would first focus on synthesizing insulin which at the time was produced from cow and pig innards
• Gilbert’s lab at Harvard was competing against them, but were bound by Asilomar restrictions because they were using a human gene. Genentech were using a chemically synthesised version which complied with NIH restrictions – this gave them a regulatory edge
• US patent act categories of inventions: the “four M’s”: methods, machines, manufactured materials, and composition of matter
• Genentech got the patent for the method of using recombinant DNA to produce a protein such as insulin or somatosin. Became one of the most lucrative patents ever with GMOs
  • Patents was the funding model that made biotech possible and Genentech pioneered that. “Patent, then publish”
  • “Over Genentech’s 40-year history, nearly 20,000 patents have been issued worldwide covering the inventions made by its researchers, as well as in its engineering and manufacturing operations”

Start of a golden age:

• “Consider this: in 1969, if a disease-linked gene was found in humans, scientists had no simple means to understand the nature of the mutation, no mechanism to compare the altered gene to normal form, and no obvious method to reconstruct the gene mutation in a different organism to study its function. By 1979, the same gene could be shuttled into bacteria, spliced into a viral vector, delivered into the genome of a mammalian cell, cloned, sequenced, and compared to the normal form.”

Part IV: Human Genetics (1970-2005)

Victor McKusick at John Hopkins University:

• By mid 80s his team had cataloged 2,239 genes linked with diseases in humans, 3,700 diseases linked to single genetic mutations. Taxonomy:
  • Monogenic (“one gene one disease”): e.g hemophelia (“the royal disease” as mutation was in Victoria’s family), sickle cell anemia
  • Polygenic: e.g Down syndrome (extra chromosome), hypertension. These with more dependence on environmental variable
• Different “penetrance”. Tay-Sachs disease, you have the mutation you will have the disease. Breast cancer (mutant BRCA1 gene) not all women will develop the cancer. Same with hemophilia.

Genetic testing & abortion:

• Since 1956 we are predicting the gender of fetuses (using cells from the amnion)
• 1968 first therapeutic abortion performed on the basis of a genetic test
• 1979 US court asserted that the right to be born free of genetic diseases is a fundamental right
• 1980 Robert Graham’s “genius sperm bank” (enhancement)

Mapping human genes & phenotypes:

• 1980s – Botstein and Davis proposed using DNA polymorphisms for large-scale systematic mapping of human genes. [I didn’t fully get how this works]
• Was used to identify a gene that causes cystic fibrosis.
  • 1/25 men and women of European descent carry the mutation.
  • “That cystic fibrosis had something to do with salt and secretions had been suspected for centuries. In 1857, a Swiss almanac for children’s songs and games warned about the health of a child whose “brow tastes salty when kissed”.
  • If CF is so lethal why wasn’t it driven out by natural selection? Belief it may have helped fight off cholera.
• Barranquitas village in Venezuela, Huntington’s disease affects 1 in 10 (it usually affects 1 in 10,000)
• Impetus for Human Genome Project came from needing to study polygenic illnesses (multiple genes) like
  • Cancer
  • Schizophrenia (very high concordance rate among identical twins)

Normal cells acquiring genes with cancer-causing mutations from:

1. Environmental damage: tobacco, UV, X-rays, which attack DNA and change its chemical structure
2. Spontaneous errors during cell-division
3. Inherited from parents (retinoblastoma, breast)
4. Carried into cells via viruses

Human genome project:

• Human Genome Project. Craig Venter led with provacative idea to sequence only gene fragments initially. Race between Celerate and NIH body.
  • Sequenced 3 females and two males, mix of heritages
• Of 289 human genes known to be involved with a disease, 177 are also present in flies.
  • Genes involved in colon cancer, breast cancer, Tay-Sachs disease, muscular distrophy, etc
• Dawkins: “the difference between a human and a nematode worm is not that the humans have more of those fundamental pieces of apparatus, but that they can call them into action in more complicated sequences and in a more complicated range of spaces.”
• Beauty in our genome
  • “Parts of it are surprisingly beautiful. On a vast stretch on chromosome eleven, for instance, there is a causeway dedicated entirely to the sensation of smell. Here, a cluster of 155 closely related genes encodes a series of protein receptors that are professional smell sensors. Each receptor binds to a unique chemical structure, like a key to a lock, and generates a distinctive sensation of smell in the brain-spearmint, lemon, caraway jasmine, vanilla, ginger, pepper. An elaborate form of gene regulation ensures that only one odor receptor gene is cho sen from this cluster and expressed in a single smell-sensing neuron in the nose, thereby enabling us to discriminate thousands of smells”
• Although we fully understand the genetic code – how the information of a single gene is used to build a protein – we comprehend virtually nothing of the genomic code – how multiple genes spread across the human genome coordinate gene expression in space and time to build, maintain, and repair a human organism.

Part V: The Genetics of Identity and “Normalcy” (2001-2015)

Naming is hard:

• Genes shouldn’t be named after the disease they may cause, eg cystic fibrosis. That would be as absurd as defining organs by the diseases they get: livers are there to cause cirrhosis, hearts to cause heart attacks, etc.
• In the last couple of decades we shifted from pathology (just studying diseases) to also studying normalcy (how stuff works, not just diseases)

Hi Mom!

• The intergenerational time between any two family members is proportional to the extent of genetic diversity between them (as mutations accumulate over generations)
• Can be generalised to populations. eg can measure oldest tribes within a population (San tribes of sub-Saharan Africa)
• Mitochondria, which contains some of our genome, is passed intact between generations (no “crossing over”) so it’s used to age populations
• Mitochondrial DNA is only passed through from the mother. Because many mothers only have sons, the number of surviving maternal lineages keeps shrinking. First one is “Mitochondrial Eve“

Would this knowledge lead to more empathy for trans people?

• Genes on the Y chromosome are the most febrile because they have no copy. It is the only single chromosome. For this reason (eg damage not repaired) has been shrinking over time
• Swyer syndrome. Biologically female but chromosomically male.
  • Most likely scenario is master-regulatory gene that specifies maleness being inactivated by a mutation. This gene was found in 1989, called ZFY
  • Another gene called SRY linked to the syndrome. Inserted it in female mice, their offspring were born anatomically male and biologically female (syndrome in reverse)
• SRY acts on dozens of genes, which in turn integrate inputs from the self and the environment (hormones, behaviors, exposures, etc) to create gender. Gender is “an elaborate genetic and developmental cascade”

No, it’s not a choice:

• J Michael Bailey twin-study experiments. Recruited 110 twins in which at least 1 was gay. Among 56 pairs of identical twins, both twins were gay in 52%. Of the 54 pairs of non-identical twins, 22% were both gay. Lower than fraction for identical twins, but still significantly higher than ~10% in overall population
• Geneticists have not found a “gay gene” but have found a few “gay locations” throughout the genome
• Found that a large share of these locations were passed through on the maternal side so had to be on X chromosome

You are writing to your genome throughout your life:

• “Does the activation or repression of genes in cells and bodies (in response to environmental inputs: a fall, an accident, a scar) leave some sort of permanent mark or stamp on the genome?” Do these marks get transmitted across generations?
• Epigenetics – “above genes” – defined by Waddington as “the interaction of genes with their environment […] that brings their phenotype into being”
• Hongerwinter study (Dutch famine in 1944-45): 1990s, found that the grandchildren of men & women exposed to the famine had higher rates of obesity and heart disease. Acute period of starvation had imprinted messages into the genomes of starving men & women.

Regulators gonna regulate:

• Late 70s discovered that the attachment of a small methyl group molecule to some parts of DNA was correlated with a gene’s turning off (so the genes are unchanged but the DNA contains changes to how they will be expressed/activated)
• 1996 David Allis discovery of changes to histones (proteins which package genes) which can change the activity of a gene.
• Protein regulators – “master conductors of the symphony of genes in cells”
• If you sequence the epigenome of twins over several decades, you find substantial differences: eg pattern of methyl groups attached to the genomes of blood or neuron cells.
• (The methyl groups on DNA are also one of the biomarkers of aging, which David Sinclair talks about)

Yamanaka, modifying our epigenome:

• 2006: Yamanaka. Could we erase these marks that get added onto the genome and restore “original” cell identity and behaviour?
• Was able to turn a mouse’s mature skin cell into an embryonic stem cell (pluripotent – that could then turn into any organ). Reversing how it usually goes
• One of the genes introduced to do this – c-myc – is also one of the most cancer-causing genes known

Part VI: The Genetics of Fate and Future (2015-)

• In 70s we tried to modify genome of mice by infecting embryonic cells with a gene-modified virus SV40
• Years later discovered that epigenetic marks had been placed on viral genes to silence them

Stem research:

• Organs regenerate their own cells via stem cells. A stem cell (1) can give rise to other functional cell type (eg nerve, skin) and (2) can renew itself.
• Embryonic stem cells can give rise to every cell type in the organism (pluripotent)
• “Transgenic animals”: gene-modified ES cells would in theory result in transmission of the gene-modification through generation (as the ES cells would produce sperm and egg cells)
• Early 90s discovered that human ES cells don’t behave themselves in culture. Slowed transgenesis down

The first human gene therapy:

• September 1990 first human gene therapy.
  • 4-year old Ashanti DeSilva who inherited two broken copies of the gene that contains the instructions for manufacturing a protein called adenoside deaminase (ADA).
  • Without it, special white blood cells called T cells die off. Without T cells, immune system deficiency syndrome (“bubble boy syndrome”)
• Received a working copy of the ADA gene delivered via a “hollowed-out” virus.
• She was also taking drugs which confounds the results of the therapy, but she had a much better health outcome than others

Jesse Gelsinger’s death:

• Jesse Gelsinger had a rare metabolic disorder called ornithine transcarbamylase deficiency syndrome, or OTCD, in which ammonia builds up to lethal levels in the blood. Had to take 50 pills per day.
• Researchers at the University of Pennsylvania in Philadelphia were developing a fix for the OTC gene, which produces an enzyme that prevents ammonia buildup
• Jesse received this gene fix via a hollowed out virus, had an intense inflammatory response, and was dead within 4 days.
• “That made the whole field of gene therapy go away, mostly, for at least a decade.” – Doudna

Diagnosis & previvors:

• While “genetic alteration” (modifying genes to combat a disease) had a big setback with Gelsinger’s death, “genetic diagnosis” (reading genes to predict or determine illness, identity, etc) was growing from strength to strength
• Breast cancer gene BRCA1. Genetic test began being marketed in 1996.
  • Women with a BRCA1 mutation have an 80% lifetime risk of breast cancer.
  • But we don’t know when they might have it, or what type of cancer.
  • “Previvors” – people burdened by the result of the genetic test, often not actionable
• Genetic cause for schizo-phrenia (“split brain”) uncovered through 80s from twin-studies.
  • Higher rate with older fathers. But no single gene predictor
  • 2009 Swedish study of 1000s of families, showed that bipolar disorder and schizophrenia share a strong genetic link
• We are still quite far from a genetic test for schizophrenia, we can’t yet estimate penetrance and expressivity based on given mutations being around (and therefore predict risk)
• Ethical implications of a test like this: possible link between bipolar disorder and creative talent. “Heightened creativity during throes of mania”

Pre-natal testing:

• In IVF clinics there are is now preimplantation genetic diagnosis (PGS) – grow the embryos in an incubator for a few days, and pick the one with the right characteristics to implant.
• Currently diagnosing mono-genetic diseases, and can tell sex

Moving ethical boundaries:

• Current ethical boundaries for genetic diagnosis and intervention
  1. High diagnosis accuracy: genetic variants that are singularly powerful determinants of illness (highly penetrant mutations). Down syndrome, cystic fibroris, sickle-cell anemia, Huntington’s
  2. Extraordinary suffering engendered by the diseases caused by these mutations
  3. Freedom of choice in the interventions
• But these boundaries can change.
  • e.g short variant of 5HTTLPR gene associated with higher risk of stress, more impulsive, more prone to addictions. What is the level at which it becomes “extraordinary suffering”?
  • eg studying “resilience gene”.

The germ-line editing Rubicon:

• Gene therapy applied to:
  • Non-reproductive cells: eg a blood cell, does not alter the genome more than 1 generation.
  • Reproductive cells: eg into the germ-line (a sperm, egg). Change is self-propagating.
• Technical hurdles to germ-line editing:
  1. ❌Reliable human embryonic stem cells. Research done with unused IVF embryos, progress being made but funding shut down by GW Bush administration, reopened by Obama.
  2. ✅Reliable change to the genome. Now achieved with CRISPR
  3. ✅Transfer human ES cell into human embryo. Technical and ethical implications. Likeliest approach is modifying “primordial germ cells” (that turn into sperm and egg) that will then be used to make a human embryo with IVF. Demonstrated to be doable.
• Ethical hurdles
  • ❌Mortarium in place since 2015

Misc

• “​Cancer, perhaps, is an ultimate perversion of genetics: a genome that becomes pathologically obsessed with replicating itself. The genome-as-self-replicating machine co-opts the physiology of a cell, resulting in a shape-shifting illness that, despite significant advances, still defies our ability to treat or cure it.“
• Pythagoras theorem was proven by Indian or Babylonian geometers before him.
• In 1796, Laplace proposed that the solar system arose from cooling & condensation over millions of years. Napoleon asked him why God was so conspicuously missing from his theory. “Sire, I have no need for that hypothesis”
• Darwin, Mendel, Galton – all did terribly academically
• We have about 37 trillion cells each. A worm has about 960
• Human genome encodes 20,687 genes – only 1,796 more than worms, 12,000 fewer than corn, and 25,000 fewer than rice of wheat. It has 3,095,677,412 base pairs.
• 98% of human DNA isn’t gene, it encodes no proteins or RNA. We know some regulates gene expressions, some is junk, and a lot of it we don’t understand yet.
• Our DNA is encrusted with history. Peculiar fragments of DNA which have been carried passively for millenia (watch out Arweave, here’s some permanent storage competition)
• “Progress in science depends on new techniques, new discoveries, and new ideas, probably in that order” – Sydney Brenner
• “Once the power to control genes has been harnessed, no beliefs, no values, and no institutions are safe.” – geneticist J.B.S Haldane
• Largest “negative eugenics” program is not the Nazis, but India and China, where 10M+ female children are missing from adulthood because of abortion, infanticide, neglect.

A manifesto for a Post-Genomic World

In conclusion, Mukherjee offers the following draft manifesto / “Hitchhiker’s guide” for harnessing the power of genetics. It’s a manifesto future generations will have to write and enforce.

1. A gene is the basic unit of hereditary information.
2. The genetic code is universal. There is nothing special about human genes.
   • A gene from a blue whale can be inserted into a microscopic bacterium and it will be deciphered accurately and with nearly perfect fidelity
3. Genes influence form, function, and fate, but these influences typically do not occur in a one-to-one manner.
   • Human attributes are consequence of genes, environments, and chance.
   • We can predict the ultimate effect of a mutation or variation on an organism for only a minor subset of genes
4. Variations in genes contribute to variations in features, forms and behaviors.
   • Variations we understand like “genes for height” or “gene for blue eyes” are an extremely minor part of the genome
   • 2 humans share at least 99.688 percent of their genome
5. When we claim to find “genes for” certain human features or functions, it is by virtue of defining that feature narrowly
   • If we define “beauty” as having blue eyes (and only blue eyes), then we will, indeed, find a “gene for beauty.” If we define “intelligence” as the performance on only one kind of problem in only one kind of test, then we will, in deed, find a “gene for intelligence.” The genome is only a mirror for the breadth or narrowness of human imagination. It is Narcissus, reflected.
6. It is nonsense to speak about “nature” or “nurture” in absolutes or abstracts.
   • The SRY gene determines sexual anatomy and physiology in a strikingly autonomous manner; it is all nature.
   • Gender identity, sexual preference, and the choice of sexual roles are determined by intersections of genes and environments-i.e., nature plus nurture.
   • The manner in which “masculinity” versus “femininity” is enacted or perceived in a society, in contrast, is largely determined by an environment, social memory, history, and culture; this is all nurture.
7. Every generation of humans will produce variants and mutants
   • The desire to homogenize and “normalize” humans must be counter balanced against biological imperatives to maintain diversity and abnormalcy. Normalcy is the antithesis of evolution.
8. Many human diseases-including several illnesses previously thought to be related to diet, exposure, environment, and chance are powerfully influenced or caused by genes.
   • More than ten thousand such diseases have been defined thus far. Between one in a hundred and one in two hundred children will be born with a monogenic disease.
9. Every genetic “illness” is a mismatch between an organism’s genome and its environment
   • In some cases, the appropriate medical intervention to mitigate a disease might be to alter the environment to make it “fit” an organismal form (building alternative architectural realms for those with dwarfism; imagining alternative educational landscapes for children with autism). In other cases, conversely, it might mean changing genes to fit environments. In yet other cases, the match may be impossible to achieve: the severest forms of genetic illnesses, such as those caused by nonfunction of essential genes, are incompatible with all environments. It is a peculiar modern fallacy to imagine that the definitive solution to illness is to change nature-i.e., genes-when the environment is often more malleable.
10. In exceptional cases, the genetic incompatibility may be so deep that only extraordinary measures, such as genetic selection, or directed genetic interventions, are justified.
    • Until we understand the many unintended consequences of selecting genes and modifying genomes, it is safer to categorize such cases as exceptions rather than rules.
11. There is nothing about genes or genomes that makes them inherently resistant to chemical and biological manipulation.
    • An epigenetic modifier may be designed to change the state of hundreds of genes with a single switch. The genome is replete with such nodes of intervention.
12. A triangle of considerations-extraordinary suffering, highly penetrant genotypes, and justifiable interventions-has, thus far, constrained our attempts to intervene on humans.
    1. These considerations will shift over time.
13. History repeats itself, in part because the genome repeats itself.
    • And the genome repeats itself, in part because history does. The impulses, ambitions, fantasies, and desires that drive human his tory are, at least in part, encoded in the human genome. And human history has, in turn, selected genomes that carry these impulses, ambitions, fantasies, and desires. This self-fulfilling circle of logic is responsible for some of the most magnificent and evocative qualities in our species, but also some of the most reprehensible. It is far too much to ask ourselves to escape the orbit of this logic, but recognizing its inherent circularity, and being skeptical of its overreach, might protect the weak from the will of the strong, and the “mutant” from being annihilated by the “normal.”

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We are as Gods, and have to get good at it.

– Stewart Brand