30/01/2017
John Langley 1852-1925
 Advanced the idea of ‘receptive substances which
were where drugs worked
 These were specific entities which could distinguish
between things like nicotine and muscarine,
strychnine and atropine
 People working on this issue were all physiologists
who had developed various preparations, isolated
heart, guinea pig ileum, various ganglial
preparations
 Langley’s experiments made extensive of denervated
frog preparations. This involved exposing the target
muscle in the whole animal, severing the nerve and
allowing it to atrophy and then returning to the
animal some days later
 This would allow an exploration of the
neurotransmitters mediating the various responses –
and – exploration of drugs that might mimic or block
the effect of the original nerve – e.g. Adrenaline,
curare, strychnine, acetyl choline etc
(J. Physiol., 1905)
 Langley did not explicitly propose that his receptive
substances were on the surface of his preparations,
but since he was applying his drugs locally with
micro-pipettes and getting effects distally and
rapidly to denervated tissues he inferred that the
receptive substances were at the surface – but no
explicit proof
 A theory was advanced that nerve conduction
involved two nerve parts - pre-ganglial sections,
which were all similar and post-ganglial sections
which were specific to the target of the particular
nerve
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30/01/2017
Two neurones in series
Two divisions: sympathetic and parasympathetic
Postganglionic
fibre
Ganglia
ANS
Preganglionic fibre
They differ in the site in
the CNS in which the cell
body of the
preganglionic neurone is
located.
M
Parasympathetic cranial
outflow
C
T
Sympathetic
thoracolumbar outflow
L
S
Sympathetic division
Effectors
Effectors
Structures in
Head and neck
T
Heart
Coeliac
ganglion
Adrenal medulla
L
Blood vessels
Stomach
Liver
GI tract
Sweat glands
Show this to demonstrate
that knowing the anatomy
allowed dissection of the
Neurotransmission and potential
sites of action for drugs
Bladder
Kidney
Genitalia
Hypogastric
ganglia
Identification of chemical transmitters
within the ANS
1905 Langley : Nicotine mimics preganglionic fibre activation.
Drugs acted on “receptive substance”.
Sup mesenteric
ganglion
Lungs
Parasympathetic sacral
outflow
Prevertebral ganglia
1915 Elliot, Langley and Dale: two substances were known (ACh and NA)
with actions reproducing those of the two main divisions of the
autonomic system
1921. Loewi discovered ‘Vagusstuff’ - Acetylcholine
1933: Feldberg showed that ACh was released from all preganglionic
fibres.
1935: Dale suggested that neurons release the same transmitter at all
their axon terminals – a very conservative system – so that it was the
innervation that was specific, not particularly the neurotransmitters.
(A striking contrast to hormones as it turned out)
Two neurones in series
Ganglia
Postganglionic
fibre
ANS
Preganglionic fibre
Acetylcholine
released
So, understanding neurotransmission as being mediated by
both electrical and precise chemical mechanisms demystifies
some of the most complex behaviours of the whole organism
(or at least isolated organs) and the ability to manipulate
neurotransmission chemically with defined drugs opens the
door to further engagement with biological complexity
 Nevertheless at the beginning of the 20th century, it
Noradrenaline
released
was still possible to believe that living entities
(comprising living cells) possess different properties
from non-living material
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30/01/2017
The end of Vitalism
Natural compounds were strange
 Biological compounds were unusual (e.g. urea, amino acids)
characteristically ‘biological’ – rather than the easily
synthesized chemicals of the time, optical isomers and some
impossibly complex e.g. Phenylalanine, Morphine, etc or
quite beyond comprehension – DNA, proteins and complex
carbohydrates etc
 Surrounds biology with a mystical and
unapproachable aura.
 Not surprising that elements of ‘vitalism’ survived
– living organisms possessed unique synthetic
abilities that depended on the intact organism
Fermentation – allows the breakthrough
Known since ancient times – the effect of a mass of yeast – (Greek;
zyme) on cereal dough with the evolution of gas and change in the
texture of the solid matter for breadmaking. In addition when
crushed fruits e.g. Dates were stored a material with a mildly
intoxicating effect was produced. But with longer time the liquid
turned sour and yielded vinegar, the strongest acid known in
antiquity. This souring of wine was considered comparable to the
souring of milk. By 1500BC the use of cereals to produce beer and
wines were established arts in Mesopotamia and Egypt (and
elsewhere).
These ancient arts provoked speculation by Greek natural philosophers
on the nature of fermentation – zymosis, and putrefaction – sepsis.
Aristotle’s followers would see fermentation as maturation, and
sepsis as death
Enzymes
 First recognition of an enzyme was made by Payen and Persoz 1833
(Annales de Chimie) - an alcohol precipitate of malt extract
produced a thermolabile substance which converted starch into
sugar, a process they termed diastasis (diastasiz) – separation –
suggested by separation of soluble dextrin from the insoluble
envelopes of the starch grains
 [Note that at this early stage they had a quantitative method for
estimating starch concentration (it yielded a blue colour with iodine)
so they could begin to be quantitative with regard to activity and
richness of sources and stability of the enzyme – the essential
ingredioent for an enzyme assay]
 Later, the name diastase was generally applied to enzymes and
ultimately the suffix -ase was added to the root of whatever the
substance was on which enzymes acted
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30/01/2017
 Because of the parallelism between the action of enzymes and
that of yeast the name ‘ferment’ was used for enzymes
 In the latter half of the 19th century there were arguments
between Pasteur and Liebig where Liebig held that
fermentation and similar actions were due to the actions of
chemical substances and Pasteur who held that fermentation
was inseparable from living cells
 Justus Liebig (1803-1873) – a few words
 Considered the father of organic chemistry
 Liebig not only isolated numerous individual substances, but also studied
their interrelationships and the ways in which they degraded and
metamorphosed into other substances, looking for clues to the
understanding of both chemical composition and physiological function.
Other significant contributions by Liebig included his examination of the
nitrogen content of bases; the study of chlorination; the identification of the
ethyl radical (1834); the oxidation of alcohol and formation of aldehyde
(1835); and the degradation of urea (1837).
 Writing about the analysis of urine, a complex organic product, he made a
declaration that reveals both the changes that were occurring in chemistry at
that time and the impact of his own work........ At that time when many
chemists such as Jöns Jakob Berzelius (1779-1848 Swedish; credited with
the discovery of Si, Th, Ce and Se; also with the law of definite proportions
e.g. H2O for water etc) still insisted on a hard and fast separation between
the organic and inorganic,.............
 As in.......... those compounds that were formed from four elements alone—
carbon, oxygen, hydrogen, and nitrogen—were “organic,” because they
always seemed to be the products of living beings composed of complex yet
highly organized systems. The thinking was that such substances could not
be created in the laboratory from inorganic materials, and thus a “vital
force” beyond the understanding of chemists was necessary to explain their
existence.
 However Liebig proposed "The production of all organic substances no
longer belongs just to living organisms. It must be seen as not only probable,
but as certain, that we shall be able to produce them in our laboratories.
Sugar, salicin, and morphine will be artificially produced. Of course, we do
not yet know how to do this, because we do not yet know the precursors
from which these compounds arise. But we shall come to know them."
 — [Liebig and Woehler (1838)]
 Indeed his colleague Woehler accidentally discovered the synthesis of urea.
Wöhler is regarded as a pioneer in organic chemistry as a result of his
(accidentally) synthesizing urea from ammonium cyanate in the Wöhler
synthesis in 1828. This discovery was celebrated as a refutation of vitalism,
However, contemporary accounts do not support that notion. This Wöhler
Myth, as historian of science Peter J. Ramberg called it, originated from a
popular history of chemistry published in 1931, which, "ignoring all pretense
of historical accuracy, turned Wöhler into a crusader who made attempt
after attempt to synthesize a natural product that would refute vitalism and
lift the veil of ignorance, until 'one afternoon the miracle happened'".
Nevertheless, it was the beginning of the end of one popular vitalist
hypothesis, that of Berzelius that "organic" compounds could be made only
by living things
 So the battle on vitalism became more crystallised and explicit
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30/01/2017
Buchner’s Breakthrough
 Eduard Buchner was awarded the Nobel Prize in 1907 for showing
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that a cell-free extract of yeast could ferment sugars.
In a major blow to vitalism he showed that living yeast cells were
not needed for fermentation. He made a cell-free filtered extract
by pulverizing dry yeast cells with an abrasive silica-like mixture
in a pestle and mortar. The resulting "press juice" had sugars added
and carbon dioxide evolved for long periods
Microscopic investigation revealed no living yeast cells in the
extract.
Thus a living process could be observed independently of life.
A massive expansion of ‘Biochemistry and ‘Enzymology’ was
incorporated into this non-vitalist view of Biology
Transition from Vitalism to Organicism
John Scott Haldane adopted an anti-mechanist approach to biology and an idealist
philosophy. Haldane saw his work as a vindication of his belief that teleology was an
essential concept in biology. His views became widely known with his first book
Mechanism, life and personality in 1913. Haldane borrowed arguments from the
vitalists to use against mechanism; however, he was not a vitalist. Haldane treated the
organism as fundamental to biology: "we perceive the organism as a self-regulating
entity", "every effort to analyze it into components that can be reduced to a mechanical
explanation violates this central experience". The work of Haldane was an influence on
organicism – i.e. that components do not tell you what the organism can do – it is all
the feedbacks between the components which define the organism
 Haldane also stated that a purely mechanist interpretation can not account for the
characteristics of life. Haldane wrote a number of books in which he attempted to show
the invalidity of both vitalism and mechanist approaches to science. Haldane
explained:
 “We must find a different theoretical basis of biology, based on the observation that all
the phenomena concerned tend towards being so coordinated that they express what is
normal for an adult organism”
 So Haldane saw himself as both an anti-vitalist and an anti-reductionist - organicist
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