From Darwin to Drug Resistance - bsac.org.ukbsac.org.uk/.../2012/02/Laura-Piddock_From-Darwin-to-drug-resistance.pdf · From Darwin to Drug Resistance Written by Professor Mark Pallen

From Darwin to Drug Resistance

Written by

Professor Mark Pallen

Presented by

Professor Laura Piddock

Both of The University of Birmingham

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

EvolutionOrigin 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…

“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.”

Variation precedes Selection

“Some authors have declared that natural selection explains nothing, unless the precise cause of each slight individual difference be made clear. Now, if it were explained to a savage utterly ignorant of the art of building, how the edifice had been raised stone upon stone, and why wedge‐formed fragments were used for the arches, flat stones for the roof etc.; and if the use of each part and of the whole building were pointed out, it would be unreasonable if he declared that nothing had been made clear to him, because the precise cause of the shape of each fragment could not be given. But this is a nearly parallel case with the objection that selection explains nothing, because we know not the cause of each individual difference in the structure of each being.

The shape of the fragments of stone at the base of our precipice may be called accidental, but this is not strictly correct; for the shape of each depends on a long sequence of events, all obeying natural laws; on the nature of the rock, on the lines of deposition or cleavage, on the form of the mountain which depends on its upheaval and subsequent denudation, and lastly on the storm or earthquake which threw down the fragments. But in regard to the use to which the fragments may be put, their shape may be strictly said to be accidental. And here we are led to face a great difficulty, in alluding to which I am aware that I am travelling beyond my proper province. An omniscient Creator must have foreseen every consequence which results from the laws imposed by Him. But can it be reasonably maintained that the Creator intentionally ordered, if we use the words in any ordinary sense, that certain fragments of rock should assume certain shapes so that the builder might erect his edifice?” Descent of Man, 1871

The Germ Theory of Infection

1860s Louis Pasteur refutes the theory of spontaneous generation

1870s Ferdinand Cohn and Robert Koch establish pure cultures of bacteria

Koch links anthrax to presence of bacteria

Cohn founds bacterial taxonomy

1880s Discovery of Cholera, diphtheria, antiserum

Darwin and Pasteur

Pasteur vs. PouchetSpontaneous generation (heterogeny) vs. abiogenesis

“I have seen something about the infusorial experiments in Paris: Quatrefage objected to their accuracy. Some old experiments were several years ago tried in Germany with astonishing precautions (air all passed through sulphuric acid & caustic potash) & infusoria never appeared.”Letter, Darwin to Lyell 1860“I am very glad that you are going to allude to Pasteur; I was struck with infinite admiration at his work”Letter, Darwin to Bentham, 1863

Darwin and Pasteur

“I hope that you will permit me to add a few remarks on Heterogeny, as the old doctrine of spontaneous generation is now called... Your reviewer believes that certain lowly organized animals have been generated spontaneously—that is, without pre-existing parents—during each geological period in slimy ooze. A mass of mud with matter decaying and undergoing complex chemical changes is a fine hiding-place for obscurity of ideas.

But let us face the problem boldly. He who believes that organic beings have been produced during each geological period from dead matter must believe that the first being thus arose. There must have been a time when inorganic elements alone existed on our planet: let any assumptions be made, such as that the reeking atmosphere was charged with carbonic acid, nitrogenized compounds, phosphorus, etc.

Now is there a fact, or a shadow of a fact, supporting the belief that these elements, without the presence of any organic compounds, and acted on only by known forces, could produce a living creature? At present it is to us a result absolutely inconceivable. Your reviewer sneers with justice at my use of the “Pentateuchal terms’’ of one primordial form into which life was first breathed’’ in a purely scientific work I ought perhaps not to have used such terms; but they well serve to confess that our ignorance is as profound on the origin of life as on the origin of force or matter.”

Darwin Letter to Athenaeum, 1863

Darwin and Pasteur

“It is often said that all the conditions for the first production of a living organism are now present, which could ever have been present. But if (and oh! what a big if!) we could conceive in some warm little pond, with all sorts of ammonia and phosphoric salts, light, heat, electricity, &c., present, that a proteine compound was chemically formed ready to undergo stillmore complex changes, at the present day such matter would be instantly devoured or absorbed, which would not have been the case before living creatures were formed.”

Letter to Hooker, 1871

"Great problems are in question today, keeping every thinking man in suspense: the unity or multiplicity of human races, the creation of man 1,000 years or 1,000 centuries ago; the fixity of species, or the slow and progressive transformation of one species into another...."

"Virulence appears in a new light which cannot but be alarming to humanity; unless nature, in her evolution down the ages (an evolution which, as we now know, has been going on for millions, nay, hundreds of millions of years), has finally exhausted all the possibilities of producing virulent or contagious diseases--which does not seem very likely."

An address delivered by Louis Pasteur at the "Sorbonne Scientific Soirée" ofApril 7, 1864

Darwin, Cohn and Koch

Down | Beckenham Kent Jan 3. 1878.

My dear Sir.

I thank you sincerely for your most kind letter & I return your wishes for the new Year with all my heart Your letter has interested me greatly. Dr Sanderson showed me some admirable photographs onglass by Dr Koch of the Organisms which cause Splenic fever. but your letter & the valuable work which you have given me make thecase much clearer to me. I well remember saying to myself between 20 & 30 years ago, that if ever the origin of any infectious disease could be proved, it would be the greatest triumph to Science; & now I rejoice to have seen the triumph.

With respect to the filaments of Dipsacus---- I do not for a minute put my judgment on a par with yours, or that of de Bary. but my son has lately made some observations which incline me very strongly to believe that the filaments consist of living matter of the nature of protoplasm.---- Hearing from Dr Sanderson that thymol has a fatal effect on low organisms, he tried solutions of 1/10 & 1/20 both of which cause contraction of the filaments, on the other hand 1/2 solution of carbolic acid does not cause contraction, 1 does so, this agrees with several observers who find I believe that 1/2 of carbolic solution is not poisonous to microzymes.---- My son finds that strong solutions of NaCl cause contraction but not death, as thefilaments recover themselves in water; & do not swell up into bladders as they do after poisons; this agrees with H. de Vries work on the plasmolysis of cells.---- With cordial thanks & much respect.

I remain. my dear Sir.

Yours sincerely.

Charles Darwin.

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’

Adaptation or Selection?

“The influence of the substrate on the production of organisms possessing the [enzymes] may be pictured as either (1) a natural selection, or (2) a chemical adaptation. In the former case, one must suppose that there exists in all cultures a small but definite number of cells possessing the enzyme . . .

Enzymes, then, arising by some such mutation become, according to this hypothesis of natural selection, of biological value to the organism. Those members possessing them are therefore at an advantage and tend to multiply at the expense of the others. A strain is thus formed in which the majority of the members possess the enzyme in question…

More plausible is the second suggestion, that of chemical adaptation. On this view, an adaptive enzyme arises as a response to its chemical environment. It would then partake of the nature of an acquired character in higher organisms. With the removal of the stimulus, the character is lost by the descendants of the organism.”Yudkin 1932

But what about bacteria? Are they even genetic entities?

“They have no genes in the sense of accurately quantized portions of hereditary substance; and therefore they have no need for the accurate division of the genetic system which is accomplished by mitosis. The entire organism appears to function both as soma and germplasm and evolution must be a matter of alteration in the reaction system as a whole. That occasional ‘mutations’ occur we know, but there is no ground for supposing that mutations are similar in nature to those of higher organisms, nor, since they are usually reversible according to conditions, that they play the same part in evolution”Julian Huxley, 1942

Luria-Delbruck experiment, 1943

Luria-Delbruck experiment, 1943

Max Delbrück and Salvador Luria showed that mutations arise in the absence of selection, rather than in response to selection; also showed that natural selection applies to bacteria.

Inoculated a small number of bacteria into separate culture tubes.

After growth, equal volumes plated on to phage agar.

If resistance caused by a spontaneous activation then each plate should contain the same number of resistant colonies.

Instead, constant rate of random mutations in each generation means number of resistant colonies varies dramatically, sometimes hitting “jackpot”.

The fluctuation test

jackpotjackpot

Selection and Antibiotic Resistance

Resistance identified soon after development of antibacterial agents

to sulfonamide 1939

to Penicillin 1941

to streptomycin 1946

Induction or selection?

1945, Milislav Demerec applies fluctuation test to penicillin resistance in S. aureus

“Thus penicillin acts as a selective agent which suppresses the growth of non-resistant bacteria”

Dobzhansky integrates bacteria into evolutionary genetics

Dobzhansky includes a section on ‘Mutation and selection in microorganisms’ in his 1951 edition of Genetics and the origin of species

“Occurrence of changes in bacterial strains has been known for about half a century, but their interpretation had a Lamarckian flavor, as implied by the words ‘dissociation,’ ‘adaptation,’‘training,’ etc., used in this connection. It took the brilliant analysis by Luria and Delbruck (1943) and by Demerec and Fano (1945) to open this field for genetic study.”

“Demerec (1945) and Luria (1946) showed that penicillin-resistant strains of Staphylococcus aureus arise by mutations which survive in the presence of enough penicillin in the medium to kill most individuals of the parental strain. Resistance to very high doses of the drug can be built by summation of several mutational steps. This accounts for the gradual adaptation of bacterial strains to unusual environments, which was known in bacteriology for a rather long time but was misinterpreted in a Lamarckian fashion.”

Jacob-Monod model 1961

Ongoing debates: fitness costs

Ongoing debates: predictability

Ongoing debates: origins of the resistome

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