bio380 cancer phylogenomics
DESCRIPTION
Bio380 lecture on cancer as an evolutionary process, showing descent with modification, branching evolution and natural selection; focus on genome evolutionTRANSCRIPT
PROFESSOR MARK PALLEN
The Phylogenomics of Cancer
Charles Darwin 1809-1882
Shrewsbury; Edinburgh; Cambridge (1809-31)
Beagle voyage (1831-36)London (1836-42) Down House (1842-1882)
Geology; Zoology; Barnacles Voyage of the Beagle, 1839
Evolution Origin of Species, 1859 (“one
long argument”). Descent of Man, 1871
Natural SelectionNatural Selection
Fecundity of NatureStruggle for ExistenceFecundity of Nature
Struggle for Existence
Darwin’s Theory of Evolution
Newton’s law-governed
universe
Hutton and Lyell’s deep time and
uniformitarianism
The Beagle voyageFossils and biogeography
Family tradition of religious dissent
and r/evolutionary ideas
Paley’s Natural Theology
Humboldt’s adventures in natural history
Malthus Essay on Population
Scottish enlightenmentSmith’s Invisible Hand
Wallace’s letter
Mutability of SpeciesVestigial features
Mutability of SpeciesVestigial features
Non-Progressive Branching Evolution
Non-Progressive Branching Evolution
Evolutionary GradualismEvolution of complex organs
Nature rich in variety, poor in innovation
Evolutionary GradualismEvolution of complex organs
Nature rich in variety, poor in innovation
Population ThinkingBlurred boundaries
between species and varieties
Population ThinkingBlurred boundaries
between species and varieties
ExtinctionImperfection of fossil record
ExtinctionImperfection of fossil record
VariationReproduction
Selection
VariationReproduction
Selection
Sexual SelectionSexual Selection
Principle of divergenceTaxonomy as Genealogy
Tree of Life: Common DescentHomology equals similarity
from common ancestry
Principle of divergenceTaxonomy as Genealogy
Tree of Life: Common DescentHomology equals similarity
from common ancestry
BiogeographyGeography reflects genealogy
Dispersal and Adaptive Radiation
BiogeographyGeography reflects genealogy
Dispersal and Adaptive Radiation
Natural Selection
Non-Progressive Branching Evolution
Evolutionary Gradualism
Natural Selection…
“Owing to this struggle for life, any variation, however slight and from whatever cause proceeding, if it be in any degree profitable to an individual of any species, in its infinitely complex relations to other organic beings and to external nature, will tend to the preservation of that individual, and will generally be inherited by its offspring. The offspring, also, will thus have a better chance of surviving, for, of the many individuals of any species which are periodically born, but a small number can survive.
I have called this principle, by which each slight variation, if useful, is preserved, by the term of Natural Selection, in order to mark its relation to man's power of selection. We have seen that man by selection can certainly produce great results, and can adapt organic beings to his own uses, through the accumulation of slight but useful variations, given to him by the hand of Nature. But Natural Selection, as we shall hereafter see, is a power incessantly ready for action, and is as immeasurably superior to man's feeble efforts, as the works of Nature are to those of Art.”On the Origin of Species, 1859
Natural Selection… without genetics
“Our ignorance of the laws of variation is profound. Not in one case out of a hundred can we pretend to assign any reason why this or that part differs, more or less, from the same part in the parents.”
From Mendel to the Modern Synthesis
Mendel’s experiments on peas in 1860s Rediscovered in 1900s
Soma/germ-line distinction (Weismann) Chromosomes; mutations Twilight of Darwinism; persistence of “Lamarckianism” 1940s:
“Modern Synthesis” of Evolution and Genetics ‘Mendel meets Darwin’
Spectrum of genome evolution
Homo neanderthal
ensis
Extinct hominins
Living primates
Homo sapiens
Cancer evolution
What is Cancer?
Cancers or malignant neoplasms occur in multicellular organisms when a group of cells displays uncontrolled growth, invasion ± metastasis
By contrast benign tumours are self-limited and do not invade or metastasize
Cancer cells are cheaters on the contract between genomically identical cells to create multicellular bodies to propagate the germ line
Six hallmarks of cancer
1. self-sufficiency of cells in signals controlling growth
2. loss of sensitivity to antigrowth signals3. evasion of apoptosis via mutation or loss of
gatekeeper genes4. development of limitless replicative potential,
usually via the expression of telomerase5. sustained angiogenesis, whereby the blood
supply to a tumor is augmented6. tissue invasion and metastasis
Simple views of cancer
Nowell, 1976
Nowell, 1976
Cancer as an evolutionary process
Descent with Modification
Branching Evolution
Natural Selection in Cancer
Three prerequisites are necessary and sufficient for evolution by natural selection :1. Individual variations exist in the population2. These variations are heritable3. Variations in individuals lead to differential survival
and reproduction
Natural Selection in Cancer
Cancer composed of billions of malignant cells descended from single progenitor all carry somatic mutations present in founder cell additional mutations acquired by generations of daughter
cells during tumour progression genomic instability fuels genetic intra-tumour heterogeneity
Diversification into subclones, which compete for resources, such as oxygen, vascular supply, growth signals and vary in growth rate, invasiveness etc
Natural selection drives selective sweeps and adaptation to local micro-environments
Artificial Selection in Cancer
Development of resistance to cancer chemotherapeutics governed by Darwinian natural selection, an inevitable consequence of genetic diversity and selective pressure.
Artificial Selection in Cancer
Cancer stem cells with genetic instability: the best vehicle with the best engine for cancer E Lagasse
Evolution of the Cancer
Genome
~1% of our coding genes, >350 genes, can, as mutants, contribute to cancer clone evolution
Driver mutationsDriver mutations Passenger mutationsPassenger mutations
Contribute to oncogenesis; provide growth advantage; selected for in micro-niche
Occur in oncogenes (gain of
function mutations) or tumour-suppressor genes
(loss of function mutations)
Neutral mutationsCarried along for the
ride somatic mutations without
functional consequences often occur during cell division
PLUS huge increase in mutation rate with loss of genome repair mechanisms
Passengers and Drivers
Why Cancer?
Different types of causation within a causal chain Epidemiologists say cigarette tar causes lung cancer Molecular biologists say gene mutations cause lung
cancer
Mechanistic versus evolutionary causation Evolutionary or Darwinian medicine
Why is cancer common especially in humans? one in three lifetime risk
Why Cancer?
cancer as reversion to unicellular selfishness multicellularity requires the social
cohesion of cells and the severe prohibition of clonal escape
cancer as intrinsic fallibility that escalates with increasing complexity and longevity intrinsic mutability and recombination
capacity of DNA incomplete fidelity of repair
Why Cancer?
Disposable soma flaws or trade-offs apparent only in old age
tolerated so long as they do not impact deleteriously on reproductive fitness
Cellular attributes required for cell cycle, viviparity and embryogenesis available for co-option by malignant cells e.g. immunological tolerance; motility, chemotaxis,
migration and invasiveness
Stem cells retain intrinsic competence for transient, selfish replication
Why Cancer?
Stone age genome versus 21st century lifestyle pale skin provides more vitamin D, but leads to cancer
in e.g. white Australians with sun exposure breast and ovarian cancer arise from mismatch
between hunter-gatherer reproductive physiology and modern reproductive and breast-feeding choices
prostate cancer as sides effect of large prostate driven by need for sperm production matched to non-seasonal oestrus
Why Cancer?
No eyes to the future…Darwinian natural selection operates on a
“what works best today” basis. selects genetic variants from the limited
options available that best fit the prevailing conditions.
winners today can become losers tomorrow: cancer cells kill their host!
Genome evolution in Chimps, Humans, Cancers…
Genome evolution in Chimps, Humans, Cancers…
Structural alterations linked to single-nucleotide changes across different time scales in somatic- and germ-cell lineages at species level in personal genomes in human cancer cell populations
Proposed explanation low fidelity of non-replicative error-prone repair
polymerases, used during insertion or deletion, results in break-repair-induced single-nucleotide mutations in the vicinity of structural alteration
Cancer and the birth and death of species
Henrietta Lacks 1920 -1951
African–American woman Born in Roanoke, Virginia married her first cousin,
David "Day" Lacks Moved to Baltimore County,
Maryland when David started working in shipyard
Five children: Lawrence, Elsie, David "Sonny" Jr., Deborah, and Joseph (born 1950; later changed name to Zakariyya Bari Abdul Rahman).
Henrietta Lacks 1920 -1951
Feb 1951, Lacks visits Johns Hopkins with painful lump in her cervix and bloody vaginal discharge After biopsy, diagnosed with unusually
aggressive cervical cancer Eight days later, Dr. George Gey takes
second sample from her tumour Lacks treated with radium but condition
worsens
Re-admitted on Aug 8, dies Oct 4, aged 31
autopsy shows widespread metastases
buried without tombstone in family cemetery in Lackstown, Virginia.
HeLa cellsLacks’ cells propagated by George
Gey No permission or consent as, by US
law, tissues or cells taken from patients do not belong to them
First human cell line, named HeLa, supposedly after Helen Lane or Helen Larson to preserve anonymity
Gey freely donated cells to scientific community: used to test first polio vaccine in the 1950s widely used for research on cancer,
infection, cell biology, toxicology etc in > 60,000 scientific papers (>300 new papers per month)
HeLa cells Original HeLa cells were mixed population
from biopsy, subsequently cloned in several labs strains of HeLa cells continue to evolve while grown in
cell culture total number of HeLa cells now far exceeds total number
of cells in Lacks' body HeLa cells grow like weed to contaminate many other
cell lines: coomon cause of scientific error and embarrassment
HeLa Genome is different from Lacks Genome HPV18 integration HeLa cells have modal chromosome number of 82, with four
copies of chromosome 12 and three copies of chromosomes 6, 8, and 17
American evolutionary biologist Leigh Van Valen claimed HeLa represents new species, Helacyton gartleri, based on : Chromosomal incompatibility of HeLa cells with humans Adaptation to novel ecological niche (cell culture) Immortal and expand beyond desire of human cultivators
Infectious cancers
Canine transmissible venereal tumor infectious cancer in dogs and other
canids caused by an immortal cell line
Tolerated by immune system because does not express MHC
Devil facial tumour disease infectious cancer in the Tasmanian
devil caused by an immortal cell line
Tolerated by immune system because Devils all have functionally identical MHC
Likely to cause extinction of Tasmanian Devils in the wild
Summary
Cancers present a microcosm of evolution, illustrating: Descent with modification Branching Evolution Natural Selection Artificial Selection
Various answers to Why Cancer?Similar principles may govern genome evolution
at species, population and cellular levelCancers and the birth and death of the soma and
the species
When we no longer look at an organic being as a savage looks at a ship, as something wholly beyond his comprehension; when we regard every production of nature as one which has had a long history; when we contemplate every complex structure and instinct as the summing up of many contrivances, each useful to the possessor, in the same way as any great mechanical invention is the summing up of the labour, the experience, the reason, and even the blunders of numerous workmen; when we thus view each organic being, how far more interesting—I speak from experience—does the study of natural history become!
Charles Darwin, Origin of Species, 1859
http://www.ncbi.nlm.nih.gov/pubmed/17301845,16701433,20615949,19956175,19360079,17989699,20877357,18723673,20359535,959840,15613288