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.
- Between 1990 and 2005, the cancer-specific death rate had dropped nearly 15%, but still more than half a million Americans died of it in 2005. The decline was due to prevention (lung cancer and the decline of smoking), screening (colon and cervical cancer), chemotheapy (leukemia, lymphoma, and testicular cancer).
- In 1982, Genetech unveiled the first "recombinant" human insulin; in 1984 it produced a clotting factor to control bleeding in patients with hemophilia; in 1985, it created a recombinant version of human growth hormone.
- In normal cells, the Bcr and abl genes existed separately: both were tightly regulated during cell division. In CML leukemia cells, the translocation created a new chimera - Bcr-abl, a hyperactive, overexuberant kinase that activated a pathway that forced cells to divide incessantly.
- The human genome has about five hundred kinases, of which, about ninety belong to the subclass that contains src and Bcr-abl. Every kinase attaches phosphate tags to a unique set of proteins in the cell. They act as molecular master-switches in cells - turning on some pathways and turning off others - thus providing the cell a coordinated set of internal signals to grow, shrink, move, stop, or die.
- The Human Genome Project, the full sequence of the normal human genome, was completed in 2003.
- The Cancer Genome Atlas will provide a compendium of every gene mutated in the most common forms of cancer, 10k times the volume of DNA to analyze as the HGP:
  - In specimens of breast and colon cancer, 50-80 genes are mutated, in pancreatic cancer 50-60, in brain cancer, 40-50
  - When comparing two breast cancer specimens, the set of mutated genes is far from identical
  - Some mutations are passive, bystander or passengers and have no impact on the biology of cancer. Only driver mutations play a crucial role
  - Passenger mutations occur randomly and are spread throughout the genome, but drivers strike key oncogenes and tumpor suppressors, and there are only a limited number of them in the genome
  - There are key cancer pathways, like Ras-Mek-Erk or Rb pathways, and there are perhaps only 11-15 such dysregulated pathways in a cancer cell. Maybe not all of them need to be targeted when attacking complex cancers.
- New directions include:
  - Targeted therapies against these genes
  - Cancer prevention - with better understanding of carcinogens
  - Cancer screening - with better targeting og people with known genetic mutations
  - Better understanding of cancer behavior - What allows a cancer cell to keep dividing endlessly without exhaustion or deplotion generation upon generation
- Stem cells are a tiny population of cells that are capable of immortal regeneration. All human blood, for instance, can arise from a single, highly potent blood-forming stem cell. In weeks a single such blood stem cell can replenish the enitre human organism with new blood and then, when done, goes back to sleep
- Atossa's journey:
  - In 2500 BC in Egypt, Imhotep has a name for her illness but no treatment.
  - In 500 BC in her own court she has a mastectomy
  - In 300 BC in Thrace, Hippocrates identifies her tumor as a karkinos
  - In AD 168, Galen hypothesizes a systematic overdose of black bile
  - In 1779 in London, John Hunter assigns early and late stages of cancer, with a local operation for the former.
  - In 1890 in Baltimore, she is given a radical mastectomy
  - In the early 20th C, radiation is used via X-rays
  - By the 1950s, she will have a lumpectomy followed by radiation.
  - In the 1970s, she will have surgery followed by combination chemotherapy
  - From 1986, she can have targeted therapy with Herceptin
  - By the mid 90s she can be screened earlier and then have intensive follow up screening. Her daughters can even opt for preventive surgery
  - In 2050, personalized targeted therapies may be tailored to the exact mutations detected in her genome.