The Emperor of All Maladies

Leukemia - discovered in 1845
Pernicious anemia is caused by a lack of vitamin B
More than 300bn blood cells are produced per day, but if there is a lack of folic acid then production in the bone marrow halts.
Metastasis - "beyond stillness"
Cancer asphyxiates us by filling bodies with too many cells. It is an expansionist disease, it invades through tissues, sets up colonies in hostile landscapes, seeking "sanctuary" in one organ and then immigrating to another. It lives desperately, inventively, fiercely, territorially, cannily, and defensively - at times, as if teaching us how to survive. A cancer cell is an astonishing perversion of the normal cell. Cancer is a phenomenally successful invader and colonizer in part because it exploits the very features that make us successful as a species.
Cancer is a clonal disease. Nearly every known cancer originates from one ancestral cell that, having acquired the capacity of limitless cell division and survival, gives rise to limitless numbers of descendants.
Hippocrates around 400BC - Karkinos is Greek for crab. Onkos is Greek for a mass, a load, or a burden.
For Galen, around AD 140, both cancer and depression are caused by an excess of black bile. Melancholia comes from melas (black) and khole (bile).
Autopsy comes from the Greek "to see for oneself".
Anesthesia first demonstrated in 1846.
Pasteur proposes the existence of bacteria.
1867 - discovery of antisepsis through carbolic soap.
1895 - Rontgen discovers X-rays.
1902 - The Curies discover Radium, which is seen to be attacking DNA. Marie Curie dies of leukemia in 1934.
Specificity - the ability of a medicine to discriminate between its intended target and its host.
1849 - Wöhler synthesizes urea, demolishes vitalism and proves that organic and inorganic chemistry are interchangeable.
1882 - Chemotherapy, the use of chemicals to heal the diseased body is invented by Ehrlich.
Lymphomas - cancers of the lymph glands.
In 1944, the Manhattan Project spent $100m each month at the Oak Ridge site. In 1948, Americas spent more than $126m on Coca-Cola.
1918 - Spanish flu kills 600k Americans, and 50m people worldwide.
Howard Skipper - "A model is a lie that helps you see the truth."
The blood-brain barrier is an ancient biological system that has evolved to keep poisons from reaching the brain
Sarcoma - a cancer of the connective tissues
1952 - Polio vaccine.
Dogs, humans, and lions are the only animals known to develop prostate cancer.
Endocrine system = hormonal messenger system
Palliate comes from the Latin palliare = to cloak.
By 1953, Americans smoked 3,500 cigarettes per year
In 1953, the tobacco companies publish the "Frank statement".
"Doubt is our product"
1971 - Last cigarette commercial on US TV.
The time lag between tobacco exposure and lung cancer is 30 years.
1998 - The Master Settlement Agreement (MSA) with the tobacco companies.
Carcinogenesis - a cell's journey toward malignant transformation.
1928 - Invention of the Pap smear.
1913 - Invention of the Mammography
1955 - Philip Morris introduce the Marlboro Man
Leukemia cells from the National Cancer Institute continue to grow with an "obscene fecundity" over decades.
In cancer, the cell acquires autonomous proliferation.
Genes:
- Functionally, a gene is a unit of inheritance that carries a biological trait from one cell to another or from one generation to the next.
- Physically, genes are carried within the cell in the form of chromosomes.
- Chemically, genes are composed of DNA, deoxyribonucleic acid.
- Carry instructions to build proteins - complex, multidimensional macromolecules that are the workhorses of the cell. A protein is a gene realized - the machine built from the genes instructions. The genesis of proteins from genes requires an intermediary step - ribonucleic acid, RNA.
- RNA is the working copy of the genetic blueprint, the way it is translated into a protein. Genetic information is transmitted from a cell to its progeny through a series of discrete and coordinated steps:
  - Genes, located in chromosomes, are duplicated when a cell divides and are transmitted into progeny cells
  - A gene, in the form of DNA is converted into its RNA copy.
  - This RNA message is translated into a protein which, as the ultimate product of the the genetic information, carries out the function encoded by the gene.
- This unidirectional flow of genetic information from DNA to RNA to protein is universal in living organisms, from bacteria to slime molds to fruit flies to humans and from the mid-1950s is the "central dogma" of molecular biology.
- Retroviruses, such as the Rous sarcoma virus carry a special property unprecedented in any other living organism, and can convert RNA back into DNA - reverse transcription.
  - The genes of retroviruses exist as RNA outside cells and when they infect cells, they make a DNA copy of their genes and attach the copy to the cell's genes. This DNA copy, called a provirus, makes RNA copies, and the virus is refenerated, phoenixlike, to form new viruses.
  - The virus is thus constantly shuttling states, rising from the cellular genome and falling in again - RNA to DNA to RNA ad infinitum.
  - But retroviruses would turn out to be the cause of AIDS, not cancer.
- Oncogene and anti-oncogenes - normal genes capable of causing cancer through over-activation or suppression. About a hundred have been found and they are safe until activated (or suppressed) by mutations. Typically two copies of each tumor suppressor gene exist, and both need to be suppressed by independent mutations.
  - src - a diminutive of sarcoma, activates cell division
  - ras - another gene activating cell division. Also myc, neu, fos, ret, akt.
  - rb - is a suppressor gene, an anti-oncogene, which suppresses cell division. Mutations that suppress or delete both copies of this gene can cause cancer. Also p53, VHL, APC.
- Kinase - molecular master switch within calls to activate protein functions
  - Cellular src is tightly regulated - turns on and off during cell division.
  - Viral src is permanently activated - cellular src on overdrive.
- Proto-oncogene - a normal cellular gene which can be mutated by chemicals or X-rays to cause cancer by inserting foretign genes into cells. Everyone has these proto-oncogenes in their cells, but people who are exposed to carcinogens (such as tobacco or X-rays) develop cancer at a higher rate due to the increase in mutations caused by the carcinogens.
- The Philadelphia chromosome - An abnormal version of chromosome 22 that contains a fusion of two genes, the ABL1 gene and the BCR gene, a "translocation". This fusion gene is made when part of the ABL1 gene on chromosome 9 breaks off and attaches to the BCR gene on chromosome 22. The protein made by the BCR::ABL1 fusion gene can cause immature white blood cells to grow uncontrollably and build up in the bone marrow and blood. The Philadelphia chromosome is found in the bone marrow cells of almost all people with chronic myelogenous leukemia and some people with acute lymphocytic leukemia or acute myelogenous leukemia.
  - Cancer is due to specific mutations to chromosomes. Translocations can create new genes called "chimeras"
- Cancer moves slowly via many mutations in many genes over many iterations.
- Proto-oncogenes and tumor suppressor genes sit at the hubs of signaling pathways, eg the Ras-Mek-Erk pathway, which normally control tightly regulated cell division.
- Abnormal genes govern all aspects of cancer's behavior. There are six essential alterations in cell physiology that collectively dictate malignant growth:
  - Self-sufficiency in growth signals - Pathological mitosis or an autonomous drive to proliferate, due to activation of oncogenes such as ras or myc.
  - Insensitivity to growth-inhibitory (antigrowth) signals - Inactivation of tumor suppressor genes, such as Rb, that normally inhibit growth.
  - Evasion of programmed cell death (apoptosis) - Suppression and inactivation of genes and pathways that normally enable cells to die.
  - Limitless replicative potential - Activation of specific gene pathways that render them immortal even after generations of growth.
  - Sustained angiogenesis - Acquiring the capacity to draw out their own supply of blood and blood vessels.
  - Tissue invasion and metastasis - Acquiring the capacity to migrate to other organs, invade other tissues, and colonize them, resulting in a spread throughout the body.