Books: The Gene | Siddhartha Mukherjee

The Gene book

Around this time last year, a scientist from one of the discovery research labs at Amgen visited my office to talk about finance. In particular, he was considering switching his life in the lab with a more exciting one in investment management, and wanted to know whether obtaining the CFA designation was worth his time and effort. Leaving aside the specifics of that discussion, I casually mentioned that the world of finance, with its boom-bust cycles and its stories of excess (money, drugs, sex), is a natural subject for best selling books and movies and, consequently, the student of high finance will find no shortage of material to understand its history, its main characters, and thus develop a solid mental map of this topic. Conversely, the life sciences industry did not enjoy the same attention from the publishing world and this made it way more difficult for someone like me, a non-scientist, to make sense of the scattered news articles or journal publications I come across on the subjects of scientific discovery, medicine, or healthcare management.

He left my office and I never heard from this scientist again, nor I bumped into him in our facilities… until January 2017. He showed up with a thick hardcover book under his arm. The Gene, by Siddhartha Mukherjee. "This is a good book to understand where we are today," he said.

So I read its 495 pages. It has given me the much sought sense of timeline and context and, of course, as with any good book, it has opened leads to pursue and continue my education in the realms of biology, ethics, and policy.

The book provides a historical sequence of events and discoveries in the world of genetics, starting with metaphysic postulates of Pythagoras and Aristotle, moving next to actual experimentation conducted by Gregor Mendel, all the way to the latest technologies of the present day, such as CRISPR/Cas9 and embryonic stem cell research, and their potential to cure grievous illnesses. The Gene does a great job in helping us understand not only where we are today and where we come from, but also where the arrow of the future of life sciences seems to be pointing to.

I took some notes. Here they are.

Pythagoras and Aristotle

  • Pythagoras: hereditary information, or "likeness" was carried in male semen, which collected information by coursing through different parts of the body and absorbing mystical vapors from each individual part
  • Aristotle: dismantled Pythagoras's theory by questioning, among other things, how could the female body come to be when, according to Pythagoras, all the information came only from the father. His theory: both father and mother contribute actual material to the fetus. Male semen contributed the "code", and female semen, the physical raw material for the fetus
  • Aristotle grasped the concept that the transmission of heredity was the transmission of information

Mendel - Heredity

  • Began his experiments with a collection of "true-bred" pea plants
    • True-bred: every pea plant produced exactly identical offspring
  • Cross fertilized the true-breds to create hybrids
    • Individual heritable traits (e.g., tallness vs. shortness) did not blend at all
    • Traits that were expressed in the next generation were called "dominant", those who disappeared were coined "recessive"
  • Published his paper in 1865 and went unnoticed until 1900

Darwin - Evolution

  • In 1837, he drew a diagram: perhaps all species arose like branches of a tree, with an ancestral stem that subdivided into smaller and smaller branches toward modern descendants
  • When animals reproduce, they produce variants that differ from their parents. Favorable variations survive, unfavorable variations die. Death acts as nature's culler
  • What Darwin's theory of evolution was missing was a theory of heredity: when a variant is produced, how does the variant stick and is transmitted to the next generation?
    • The theory had to produce opposing results: variation and non-variation

Eugenics

  • Championed by Darwin's cousin, Francis Galton
  • The intention and idea behind eugenics was to accelerate the selection of the well-fitted over the ill-fitted, and the healthy over the sick
    • To achieve this, Galton proposed to selectively breed the strong
  • The flaw with eugenics was that it attempted to select non hereditary traits or traits that are heavily influenced by the environment or other factors (e.g., academic performance, virtue, affability, beauty)
  • The United States took the eugenics movement to the next level by preventing "the weak" from breeding through sterilization programs
  • The Nazis went to the extreme: elimination of "the weak"
    • Pseudo-science: "Jewishness" or "Gypsyness" is carried in chromosomes, transmitted through heredity, and thereby subject to genetic cleansing

Morgan's Fruit Flies - 1910s

  • While studying mutations in fruit flies, Morgan discovered that genes travel in packs
    • Packets of information were themselves packaged into chromosomes and ultimately in cells
    • Some genes were more susceptible to crossing over, suggesting that there were further apart from each other in the chromosome
  • Conceptually, he linked two disciplines: cell biology and genetics

Thought: The gene is a theory of information, the missing link between cell biology and evolution

Modern Synthesis

  • Fusion of Mendelian heredity with Darwinian evolution that resulted in a unified theory of evolution
  • Genotype + environment + triggers + chance = phenotype
  • Genotype: an organism's genetic composition (gene, group of genes, or genome)
  • Phenotype: an organism's physical or biological attributes or characteristics (eye color, resistance to cold temperatures, etc.)
  • Environment: can affect the phenotype without touching the genes; for example: a boxer's nose
  • Triggers and chance: can affect the phenotype; for example: the BRCA1 mutation and breast cancer; it increases the risk but does not guarantee the development of cancer

DNA

  • Maurice Wilkins, Rosalind Franklin, Francis Crick, James Watson
  • One of the most influential books read by Watson and Crick: What Is Life? (Erwin Schrödinger)
  • Watson and Crick solve the three-dimensional structure of DNA in 1953 at Cambridge with the help of Rosalind Franklin's photography (X-ray diffraction technique)

Information flow:

  • DNA --> RNA --> Protein
  • Gene --> Message --> Function
  • Gene (information) -- encodes --> a Message -- to build --> a Protein (form) -- enables --> Function
  • Also: Gene (information) -- encodes --> a Message -- to build --> a Protein (form) -- that regulates --> a Gene 
  • Even better: Genes -- encode --> RNAs -- to build --> Proteins -- to form/regulate --> Organisms -- that sense --> Environments -- that influence --> Proteins, RNA -- that regulate --> Genes

Anatomists versus Physiologists

  • Anatomists describe the nature of materials, structures, and body parts. How things are.
    • Mendel, Morgan, all the way to Francis and Crick in the 1950s.
  • Physiologists concentrate on the mechanisms by which these structures and parts interact to enable functions. How things work.
    • Focus of the late 1950s and the 1970s.
    • Regulation of genes (turn genes on and off)
    • Replication of genes
    • Recombination

Cut and Paste DNA: recombinant DNA

  • Paul Berg did studies with virus SV40, a virus that could coexist peaceably with certain kinds of infected cells.
  • SV40 was an ideal vehicle to carry genes into human cells.
  • Berg managed to join the entire genome of SV40 to a piece of DNA from a bacterial virus called Lambda bacteriophage, and three genes from E. coli.
    • He called the hybrids "recombinant DNA"
  • Janet Mertz, a student of Berg's, inverted the sequence of inserting genetic material from a bacteria into a virus
    • What if, rather than viruses carrying bacterial genes, bacteria carried viral genes? Crucial technical advantage: bacteria could be used as a factory for the new gene hybrids; millions of exact replicas of a piece of DNA could be created. "Clones".
  • In 1973, Herb Boyer and Stanley Cohen refine the technique to isolate the bacteria with the recombinant DNA and multiply it

1975: Asilomar II

  • Conference organized by Berg, Baltimore, and three others.
  • New techniques had made the creation and propagation of recombinant DNA extremely easy to manage, bringing with it the risk of getting out of control
  • A group of 140 scientists drew up guidelines to ensure the safety of recombinant DNA technology
    • Established categories of risk
    • Prohibited certain types of experiments (cloning or recombination of highly pathogenic organisms)

Genentech

  • Herb Boyer and Bob Swanson (venture capitalist) launch the venture with the goal of synthesizing insulin
    • Insulin, up to this point, had been extracted from pigs and cows' pancreases at a yield of 8 ounces of insulin per 2 tons of animal parts
  • Marks the link and the transition from genetics to medicine
  • The cloning and recombination of human genes allowed scientists to manufacture proteins, and the synthesis of proteins opened the possibility of targeting the millions of biochemical reactions in the human body.

Philosophical angle: what is disease?

  • A mutation is a statistical entity, not a pathological or moral one. Doesn't imply disease, nor does it specify gain or loss of function.
  • A mutation is defined only by its deviation from the norm.
  • The definition of disease rests, rather, on the specific disabilities caused by an incongruity between an individual's genetic endowment and his current environment.

The Genome

  • In the 1980s, hundreds of individual genes had been isolated, sequenced, and cloned, but no comprehensive catalog of all genes of a cellular organism existed.
    • One particularly evident benefit of this catalog was highlighted by the isolation of disease-linked genes in humans
  • The Human Genome Project was launched in 1990 and declared complete in 2003

Mitochondrial Eve (cool concept!)

  • Each of us can trace our mitochondrial lineage to a single human female who existed in Africa ~200,000 years ago

Post Genome: Embryonic Stem Cell Research

  • A stem cell can give rise to other functional cell types, such as nerve cells or skin cells, through differentiation
  • A stem cell can also renew itself (give rise to more stem cells)
  • Embryonic stem cells (ES cells) can give rise to every type of cell of an organism
  • ES cells can be isolated from the embryo of an organism and grow in petri dishes in the lab
  • With ES cells, it is possible to make genetic changes to targeted locations in the genome, and because ES cells can give rise to every cell, one can create a new organism with a "customized" genome
    • This transgenic organism can reproduce and thus the customized genome is passed on to future generations
  • If transgenic modification of human embryos is off limits due to ethical concerns, instead, scientists could insert customized genes into non-reproductive cells (blood, neurons, etc)
    • The altered genes are not passed on to the next generation but their therapeutic effect is achieved in the individual
  • Christopher Hitchens: "Hodgkin’s disease is actually much more easily cured these days, largely owing to advances in stem-cell research which will now be halted or delayed to please the faithful." [Hitchens wrote this in 2006. Fortunately, President Obama lifted the ban on stem cell research in 2009.]

CRISPR

  • Discovered in yogurt bacteria: a molecular switchblade that recognizes viruses by their DNA sequence and cuts at specific sites in viral DNA
    • Involves two critical components:
      • 1) seeker: RNA encoded in the bacterial genome that matches and recognizes the DNA of the viruses; a mirror image of that DNA
      • 2) hitman: bacterial protein called Cas9 is deployed to deliver the lethal gash to the viral gene; Cas9 only delivers its cut after the sequence has been matched by the seeker
  • The system is "programmable"
  • When a gene is cut open, two ends of DNA are revealed and have to be repaired
    • The gene tries to recover the lost information by seeking an intact copy, typically from the other copy of the gene in the cell
    • But if a cell is flooded with foreign DNA, the gene witlessly copies the information from this decoy DNA, rather than from its backup copy

Summary of lessons and principles, or the hitchhiker's guide

  1. A gene is the basic unit of hereditary information
  2. The genetic code is universal - there's nothing special about human genes
  3. Genes influence form, function, and fate, but these influences typically do not occur in a one-to-one manner
  4. Variations in genes contribute to variations in features, forms, and behaviors
  5. When we claim to find "genes for" certain human features or functions, it is by virtue of defining that feature narrowly
  6. It is nonsense to speak about "nature" or "nurture" in absolutes or abstracts
  7. Every generation of humans will produce variants and mutants; it is an inextricable part of our biology
  8. Many human diseases -including several illnesses previously thought to be related to diet, exposure, environment, and chance- are powerfully influenced or cause by genes
  9. Every genetic "illness" is a mismatch between an organism's genome and its environment
  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
  11. There is nothing about genes or genomes that makes them inherently resistant to chemical and biological manipulation
  12. A triangle of considerations -extraordinary suffering, highly penetrant genotypes, and justifiable interventions- has, thus far, constrained our attempts to intervene on humans
  13. History repeats itself, in part because the genome repeats itself. And the genome repeats itself, in part because history does.