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History of Classical Genetics

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History of Classical
Genetics
Oren Harman, Bar Ilan University, Ramat-Gan, Israel
Ehud Lamm, Tel Aviv University, Tel Aviv, Israel
Based in part on the previous version of this eLS article ‘History of
Classical Genetics’ (2006) by Oren S Harman.
Classical genetics has its origin in the 1850s and
1860s, when the Moravian monk Gregor Mendel
attempted to formalise the rules of inheritance
governing plant hybridisation. In 1909, the Danish
biologist Wilhelm Johannsen proposed that there
are two sources of variation: one arising from the
action of the environment and the other due to
variations in Mendel’s hereditary factors – entities
Johannsen called ‘genes’. When Mendel’s laws were
rediscovered in 1900, breeding experiments were
wedded to cytological observation of chromo-
somes in the nucleus of organisms – most notably
in the fruit fly – and classical genetics was born.
The chromosome theory of inheritance that was
formulated as a result of this work stated that
genes are located linearly on chromosomes and
that chromosomal dynamics underlie the patterns
of Mendelian inheritance. Towards mid-century,
this work culminated in models of what genes do,
and what they are made of.
Introduction
Classical genetics refers to the study of the laws of heredi-
tary transmission in living organisms. It is distinguished from
molecular genetics both temporally and in emphasis: classical
genetics preceded and made possible molecular genetics insofar
as the localisation of the hereditary material and the elucida-
tion of the laws of transmission led to the examination of the
phenomena of heredity at the molecular level. It should also
be distinguished from the study of gene frequencies in popu-
lations (referred to as population genetics) and the analysis of
eLS subject area: Science & Society
How to cite:
Harman, Oren and Lamm, Ehud (February 2015) History of
Classical Genetics. In: eLS. John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0003094.pub2
eLS © 2015, John Wiley & Sons, Ltd. www.els.net
Introductory article
Article Contents
• Introduction
• Medical Men, Early Breeders, Hybridists
and Hereditarians
• Mendel and the Origins of Genetics
• The Rediscovery and Birth of Classical Genetics
• What Do Genes Do?
• What Are Genes Made of?
Online posting date: 16th February 2015
entire genomes, which is typically done using advanced compu-
tational tools (this field is referred to as genomics). Historically,
classical genetics has its origin in Gregor Mendel’s papers on
inheritance in peas, published in 1866. By the time the results
and conclusions of Mendel’s garden pea experiments were redis-
covered in 1900, more was known about the role played by the
nucleus in inheritance, and traditional breeding experiments were
now supplemented by accompanying cytological investigations
focused on the chromosomes and, initially, aimed at solving out-
standing questions relating to the mechanism of evolution. This
dual approach involving breeding and microscopy was famously
championed by Thomas Hunt Morgan and his students in the
1910s, in what became known as the Fly Room laboratory at
Columbia University. Morgan and his students focused on trans-
mission (as opposed to development and evolution) and showed
that hereditary traits expressed in the phenotypes of fruit flies
could be thought of as correlated to physical genes lined up on the
chromosomes in the fly’s nucleus, implying that genes embodied
the hereditary factors transmitted from generation to generation
and that factor and trait were not the same entity (Danish biol-
ogist, Wilhelm Johannsen, distinguished theoretically between
‘genotype’ and ‘phenotype’ in 1909). The English Mendelian,
William Bateson, had coined the term for the new science in
1905: Morgan and his crew were affecting the birth of modern
‘genetics’.
Throughout the period of classical genetics, there were empir-
ical observations of hereditary phenomena in bacteria and uni-
cellular organisms that seemed to involve the cytoplasm rather
than the nucleus and various suggestions were made regarding the
material basis for this heredity. Exhibiting non-Mendelian inher-
itance patterns, cytoplasmatic inheritance was generally thought
to happen in exceptional cases and the changed traits were discov-
ered to be stable for only a few generations compared to nuclear
inheritance. Consequently, cytoplasmatic inheritance remained
outside the typical scope of classical genetics.
Once it was shown that genes lined up on the chromosome, at
least as mathematical abstractions, could be responsible for the
transmission of physical traits between generations in organisms,
classical genetics turned to two separate, but ultimately related
problems: What do genes actually do? And what are genes actu-
ally made of? The first of these questions originated in biochem-
ical investigations of ‘inborn errors of metabolism’ in humans
initiated by the English physician, Archibald Garrod, in the first
decade of the twentieth century and, ultimately, led to the notion
1
 History of Classical Genetics
that one gene creates one enzyme or, more generally, one protein.
The second of these questions grew both out of techniques and
concepts developed in physics, such as X-ray-induced mutagen-
esis, X-ray crystallography and heredity defined as the transfer of
information, and out of classical biochemical methods, culminat-
ing in the elucidation of the structure of deoxyribonucleic acid
(DNA) by James Watson and Francis Crick in 1953. The pur-
suit of the understanding that biological function and structure
are intimately connected signalled the birth of molecular genetics
from its classical genetics origins. While molecular investiga-
tions of heredity have tended to complicate the classical picture,
especially with respect to the connections between transmission
and development, they have also succeeded in highlighting the
power of its simple models and logic. The relationship between
the two, in particular the question whether classical genetics can
be reduced to molecular genetics (in a technical sense of being
logically derivable from), has been a key question in the develop-
ment of philosophy of biology.
Medical Men, Early Breeders,
Hybridists and Hereditarians
In the eighteenth century, investigators were busy trying to settle
one of the outstanding questions relating to life: How, from the
union of male and female sperm, does an organism develop? Does
the male sperm somehow provide form to the formless matter of
the female egg, initiating a progressive transformation as Aristo-
tle had argued (the ‘epigenetic’ theory) or was a miniature of the
adult (and indeed of all adults to come) already present in the male
sperm to begin with, development consisting in mere enlargement
of the miniscule ‘animalcules’ aided by the nutrients of the female
egg (the ‘preformationist’ theory)? Interpretation remained diffi-
cult, however, and it was not until the nineteenth century that the
‘babushkian’ (miniature Russian wooden dolls in which smaller
and smaller identical dolls are encapsulated) preformationist the-
ory began to wane. It then became clear that if epigenesis is
real, hybridisation of different varieties and species of plants and
animals should give rise to new forms. Furthermore, such new
forms might affect not only the immediate offspring but also sub-
sequent generations. When Swedish taxonomist, Carl Linnaeus
(1707–1778), introduced in the 1760s the notion that hybridis-
ation occurs in nature and can produce entirely new species, a
raucous debate about the possibility of transmutation and multi-
plication of species ensued, with stark theological implications.
Attention now focused on hereditary constitution as evidence
amounted that environmental conditions did not have the power to
dramatically alter or ‘degenerate’ the characteristics of an organ-
ism; earlier theories of adaptation held that distinctive character-
istics of the breed represented adaptations to the locality in which
the breed lived. Experimental plant hybridisers and animal breed-
ers set out to test this revolutionary possibility. See also: History
of Developmental Biology
The idea that there is a single general explanation for the sim-
ilarity between parents and offspring, what we would now call
heredity, developed in the late eighteenth century through the
work of French physicians. They were primarily concerned with
2 eLS © 2015, John Wiley & Sons, Ltd. www.els.net
psychological diseases that ran in families. Particularly influential
was the voluminous work of Prosper Lucas, Traité philosophique
et physiologique de l’hérédité naturelle (1847–1850), that devel-
oped a general notion of biological heredity which went beyond
the analogy of the passing of property through generations used
heretofore. This specifically biological notion developed through
the early decades of the nineteenth century, and by 1830, the term
heredity was widespread (the English term was first used in print
in 1863). This notion united various aspects that were previously
considered distinct: inheritance of normal and pathological sim-
ilarities, species-typical and individual similarities and maternal
and paternal influences. First developed for understanding human
heredity, the notion of heredity spread to theoretical and practical
work on plants and animals.
But what were the hereditary laws governing the hybridisation
of plants and animals? Why, for one, did certain characteristics
disappear in one generation only to suddenly reappear in the
next? Why were some crosses ‘true-breeding’, whereas others
produced progeny that differed from either parent? Why was
‘inbreeding’ sometimes successful and sometimes a failure? And
what was the phenomena of heredity anyway: was it a physical
force, like gravity, a fluid or perhaps a particle or particles? Was
the contribution of egg and sperm equal or was the sperm the
main agent or perhaps merely the trigger activating the beginning
of divisions of the egg into the adult form? No one knew for sure.
As the nineteenth century unfolded, however, plant hybridisers in
particular began to define the kinds of experiments and methods
that might point to a solution to some of these questions. They
began by attacking a central problem: Were the divisions between
species truly absolute, or were species simply varieties writ large?
The stakes, both economic and agricultural, and philosophical
and religious, were very high indeed.
A leading early figure in these investigations was the German
naturalist J.G. Kolreuter (1733–1806), one of the first to carry
out experiments in hybridisation as exercises in biology rather
than for practical economic reasons. Kolreuter demonstrated, a
century before Mendel, that different characters ‘segregated’ in
the hybrid progeny, that is, different characters were inherited
independent of each other. The Englishman Thomas Andrew
Knight (1759–1838) is also of particular importance for the his-
tory of classical genetics. Knight first identified the common
garden pea as ideal for crossing experiments having grasped that
its breeding can be tightly controlled as the structure of its flow-
ers prevents pollination from outsiders; the pea would always
breed true. Knight also showed that while the progeny of a cross
between two true-breeding pea parents (F1 ) were always uniform
in appearance, a cross between the F1 s produced progeny (F2 )
exhibiting the characters present in the initial parent generation.
A generation later, in 1824, two of Knight’s compatriots, J. Goss
and A. Seton, described the phenomenon of dominance (once
again, in peas): certain traits in one parent completely overshadow
the expression of other traits in the other parent, such that, for
instance, all the progeny of a pure-bred yellow-flowered parent
and a white-flowered parent would have yellow flowers. Already
a number of important pieces of the puzzle were being assem-
bled: the early experimenters had grasped that hybridisation of
sexually compatible, yet varying, true-breeding plants – those
whose offspring really did resemble themselves when they were

self-fertilised – could go a long way in helping crack the mystery
of heredity. When the German R. Wagner (1805–1864) began to
argue at mid-century that analysing a mass of data of hybridisa-
tion experiments could be helpful, the stage was set for someone
to come along and put the pieces together. See also: Koelreuter,
Joseph Gottlieb
Mendel and the Origins of Genetics
The fact that Mendel’s paper of 1866 wallowed in obscurity until
it was rediscovered in 1900 is often mentioned to emphasise the
extent to which this pea-breeding Augustinian monk from Brno
was isolated and living in the scientific backwaters of nineteenth
century Europe. Nothing could be further from the truth. Moravia
of the mid-nineteenth century was a hotbed of plant and ani-
mal breeding (focusing on apples and sheep in particular), and
the very town whose monastery Mendel served sported two of
the most august Pomological and Oenological Associations in
Europe, with strong connections, among others, to the Horticul-
tural Society of London, of which Knight was president. Brno’s
own Natural Science Society, of which Mendel was a founding
member, included as members luminaries such as Johannes Purk-
inje, Rudolf Virchow, R.W. Bunsen and Franz Unger, some of
the greatest biologists of the age. The life circumstances that led
Gregor Mendel (1822–1884) to the monastery at Brno and that
kept him there may have been serendipitous (an injured father
who needed to be replaced on the family farm and Gregor’s inabil-
ity to replace him due to a weak constitution; the incredible failure
to pass a schoolteacher’s licensing exam despite a well-earned
physics degree from the University of Vienna – twice!), but once
settled down, there was hardly any one as prepared as Mendel
to tackle the problem of hybridisation. He was well trained in
statistical reasoning, well connected and situated in the heart of
Europe’s attempt to figure out how heredity works. Most impor-
tantly, he had the land and the peace of mind to sit down and
breed peas.
Mendel comprehended that the solution to the long-held prob-
lem of an agricultural (and therefore economic) nature, namely,
the inability to predict with precision the outcomes of hybridi-
sation of different breeds of plants, constituted the key to the
solution of a problem of much more general interest, namely,
the laws governing inheritance in all living organisms. Hav-
ing read Kolreuter, Knight and Wagner, Mendel chose Pisum
sativum – the garden pea – and set to work making thousands
of crosses from which he hoped to statistically deduce the laws
of heredity. Mendel purposely chose seven characteristics vari-
ably present in 22 distinct true-breeding varieties of the pea (seed
colour, position of flower, form of pod etc.), which he knew seg-
regated independently (there was no ‘luck’ involved as is often
intimated), and set to work between 1856 and 1864 making all the
possible crosses between them and scoring the results. The 1866
paper, Experiments in Plant Hybridization, detailed what would
later become known as Mendel’s laws: each parent contributes
one of two ‘factors’ (Anlagen) that segregate independently into
sexual gametes; the ‘gametes’ recombine in the next generation
to form an individual; it makes no difference whether a ‘factor’
is inherited from the mother or father – they both behave in the
eLS © 2015, John Wiley & Sons, Ltd. www.els.net
History of Classical Genetics
same way; when two different factors unite in the ‘zygote’, one
will be dominant and one recessive; factors for one trait assort
independently of factors for another trait. Mendel was able to
deduce these conclusions from the 3:1 dominance ratios he found
in the progeny of the crosses between F1 hybrids (i.e. in F2 s) and
the 9:3:3:1 ratios he found when breeding for two traits simulta-
neously. Albeit with one major caveat, these would serve as the
rules governing basic inheritance of simple traits in living organ-
isms. Mendel was after the essentials, not the exceptions, and that
is what he got.
For reasons that are often debated, and despite the fact that
the relevant personages of the time were aware of the paper
(with the exception of Darwin who held a copy but, alas, com-
pletely innumerate, never bothered to read it), Mendel’s results
went unnoticed for over 30 years. Significantly, however, dur-
ing this period important developments in cytology were made,
chief among them Oscar Hertwig’s description of the sperm enter-
ing the nucleus of the egg and initiating fertilisation; Walther
Flemming’s description of the stages of cell division (mitosis);
August Weismann’s postulation of the need for a reduction divi-
sion during the creation of gametes (termed ‘meiosis’ in 1905)
and the naming of the stringy nuclear constituents, the ‘chro-
mosomes’, by Wilhelm Waldeyer in 1888 (the entire set was
dubbed ’chromatin’ a few years earlier, in reference to the ability
to observe it under a light microscope using dyes). What remained
now was to figure out the correct relationship between what was
being observed in the nucleus and what Mendel had deduced from
his breeding experiments.
The Rediscovery and Birth
of Classical Genetics
In 1900, three botanists – Hugo de Vries in Amsterdam,
Carl Correns in Tübingen and Erich von Tschermak in
Vienna – independently rediscovered Mendel’s ratios. While
the extent to which each of the three men truly understood
the significance of their own discoveries is still debated, it is
clear that the public recognition of Mendel as the antecedent
constitutes a social act of attribution, with the ‘rediscovery’
in 1900 functioning as the first step. A new breed of scien-
tists – ‘Mendelians’ – now claimed knowledge of the workings
of hereditary transmission. In Amsterdam, de Vries performed
experiments on the evening primrose and concluded in 1903
that spontaneous, internal and discontinuous ‘mutations’ in the
hereditary substance constituted genetic mechanisms capable of
explaining evolution. de Vries, the Englishman William Bateson
and other leading Mendelians came to believe that Darwin’s the-
ory of evolution by natural selection was wrong on two counts:
evolution was neither gradual nor brought about by selection; it
was disruptive and motored by discontinuous, internal changes
to the hereditary material unaffected by the environment. The
Mendelians were challenged by a ‘Biometric School’ led by Dar-
win’s first cousin, Francis Galton and his student Karl Pearson,
that rejected the recourse to unseen, theoretically postulated dis-
crete factors responsible for heredity, defining heredity instead
based on perceivable, continuous and measurable physical vari-
ations in organisms. The theory of evolution itself was at stake,
3
 History of Classical Genetics
because the nature of evolution depended on the definition of
heredity. See also: Bateson, William; Pearson, Karl
Then, in 1902, Walter Stanborough Sutton, a graduate student
in Edmund B. Wilson’s laboratory at Columbia University, study-
ing the morphology of chromosomes of lubber grasshoppers,
concluded that the phenomena of germ-cell division, as observed
under the microscope, and heredity, as evidenced by Mendelian
breeding experiments, have the same essential features – that
is, purity of units (chromosomes, traits) and their independent
transmission. The significance of the insight was immediately
understood: if cytology and Mendelism were describing the same
phenomena, then the chromosomes could be the physical bear-
ers of heredity. Wilson named this surmise the Sutton–Boveri
hypothesis, and cytogenetics, the method of consistent applica-
tion of cytological observations to the results of breeding exper-
iments at the core of classical genetics, was born. Three years
later, in 1905, Wilson at Columbia and Nettie M. Stevens at Bryn
Mawr, Pennsylvania, concluded independently that sex determi-
nation was due to the segregation and reunion of the X- and
Y-chromosomes – a clear instance of a Mendelian pattern of
inheritance. This constituted strong evidence that the hereditary
material existed on the chromosomes.
In 1909, the Danish biologist Wilhelm Johannsen proposed that
there are two sources of variation: one arising from the action
of the environment on the developing organism and the other
due to slight variations in Mendel’s hereditary factors – entities
Johannsen now called ‘genes’. The ‘genotype’ was the sum of all
the organism’s genes, whereas the ‘phenotype’ were the charac-
ters it displayed, products of both the underlying genes and the
actions of the environment. Johannsen considered the genotype
as more fundamental and empirically robust than the gene: genes
were theoretical entities postulated to explain phenotypic differ-
ences that result from the whole genotype. He initially doubted
that genes were spatially discrete and separate units and remained
critical of work that reduced the genotype to a set of genes linked
on chromosomes. Mendelism constituted the study of the trans-
mission of the genes from generation to generation: ‘The elu-
cidation of the phenomena of heredity and variation’, William
Bateson had written in a letter to Darwin’s old friend Adam Sedg-
wick in 1905, ‘in other words, to the physiology of Descent, with
implied bearing on the theoretical problems of the evolutionist
and systematist, and application to the practical problems of the
breeders, whether of animals or plants’. This was the definition of
what the Mendelians were after, and Bateson called it ‘genetics’.
The name stuck.
In 1905, Bateson and his collaborators had discovered a trou-
bling exception to Mendel’s laws: certain traits appeared more
frequently than expected in tandem and were passed down to
the next generation together. Free assortment, it seemed, did not
always hold true: certain traits were ‘linked’. Across the Atlantic,
in the laboratory adjacent to Wilson’s at Columbia, Thomas Hunt
Morgan had began a research programme based on the breed-
ing and cytological investigation of the chromosomes of the fruit
fly Drosophila melanogaster, initially aimed at figuring out how
heredity could explain evolution. In 1910, Morgan observed in
some of the flies a heritable mutation – a white eye instead of
the normal red – and, together with his three graduate students,
Calvin Bridges, Hermann Muller and Alfred Sturtevant, went on
4 eLS © 2015, John Wiley & Sons, Ltd. www.els.net
to demonstrate a number of other characters similarly transmit-
ted by genes. Marshalling the Belgian cytologist and Jesuit priest
Frans Alfons Janssens’ observation of homologous chromosomes
wrapping around each other during meiosis to create cross-like
structures termed ‘chiasmata’, Morgan now immediately under-
stood that here was the cytological corollary to a genetic theory
of crossing-over, and the true explanation of Bateson’s ‘linkage’.
If genes were lined up along the chromosome, like beads on a
string and if homologous chromosomes exchanged genetic mate-
rial (crossing-over) during the process of gamete formation as
Janssens had thought, then it stood to reason that genes that were
close to each other on the chromosome (i.e. that were linked)
would have a better chance of passing on together to the same
gamete than genes that were further apart. The frequency with
which independent assortment of phenotypic traits occurs could
provide a measure of the relative physical closeness of the genes
on the chromosome. On the basis of this logic, Morgan and his
students used frequency data (a statistical measure) to draw the
first genetic maps, that is, to plot the physical position of fly
genes along their chromosomes. The book Morgan et al. pub-
lished in 1915, The Mechanism of Mendelian Heredity, became
the tome of classical genetics, powerfully establishing the notion
that chromosomes are the physical bearers of heredity, genes are
distributed linearly along them and crossing-over and recombi-
nation between such genetic elements takes place during meiosis
and is a potent source of genetic variation. See also: Bridges,
Calvin Blackman; Genetic and Physical Map Correlation;
Linkage and Crossing over; Morgan, Thomas Hunt; Muller,
Hermann Joseph; Sturtevant, Alfred Henry
There remained the matter of the nature of evolution. If
heredity was particulate and discontinuous as Morgan and the
geneticists had shown, how was it that many traits were observed
to be continuous and gradual, as the biometricians amply demon-
strated? The solution was ingenious: unlike Mendel’s simple
model whereby one ‘factor’ determines on trait, many characters
in organisms are determined by a number of small genes; they
are ‘polygenic’. Polygenic inheritance produces traits that look
as if they are blending and continuous, when in fact they are
determined by the actions of an aggregate of underlying, particu-
late genes. Part of the story of the grand ‘evolutionary synthesis’,
affected by leading investigators, such as R.A. Fisher, J.B.S.
Haldane and Sewell Wright, was to show that both the
Mendelians and the Biometricians held a piece of the truth:
evolution is normally gradual, working on continuous pheno-
typic traits, yet variation is based on discrete changes – mutations,
recombination and so on – to the underlying genes residing at
the cellular level. In 1933, Morgan was awarded the Nobel
Prize in physiology or medicine for his pioneering work in
the establishment of classical genetics. See also: Dobzhansky,
Theodosius; Evolution: History; Haldane, John Burdon
Sanderson; Wright, Sewall
What Do Genes Do?
If the models of classical genetics had been successful in describ-
ing the process of genetic transmission, they had nonetheless said
little about what genes actually do. If factor and trait are not

synonymous, then what is it that the factor does in order to bring
about the trait? Morgan and his Fly Group, and to a great extent
much of American genetics, had made a conscious decision to
focus, at least experimentally if not in thought, on transmission
genetics (how genes are passed from generation to generation) at
the expense of development (how genes play a role in affecting
the growth of an individual organism). Recent historical schol-
arship has shown that this narrative tends to exclude the much
broader conception of genetics practised in Germany in partic-
ular, where physiological and developmental genetics remained
central investigations throughout the first half of the twentieth
century. Moreover, members of the Morgan circle used the power-
ful tools they developed for studying fruit-fly genetics to address
development, evolution and other biological questions that went
beyond laws of transmission. Mid-century classical genetics,
however, is often perceived as a science of transmission genet-
ics, concerned primarily with explaining patterns of inheritance.
It was in England, and from the unexpected quarter of medicine,
that the first important clues about gene action emerged. Treating
patients afflicted with alkaptonuria, a disorder that causes painful
arthritis later in life, the physician Archibald Garrod showed that
the disorder followed a Mendelian pattern of inheritance and
manifested itself in the absence of an enzyme specialising in the
breakdown of homogentistic acid (which is excreted in the urine
of alkaptonuria patients, and which turns black upon exposure to
air – the telltale sign of affliction with the disorder). As the pat-
tern of inheritance of the disorder suggested that a single recessive
gene was at work, Garrod deduced that the failure to synthesise
the enzyme must be due to a defect in the gene. In a lecture to
the Royal College of Physicians in 1908, Garrod suggested that
alkaptonuria was an ‘inborn error of metabolism’, and coined the
adage ‘one gene, one enzyme’ to describe what genes actually do.
See also: Genes: Definition and Structure
Garrod’s deduction was lent further support in the 1940s, in
Nobel Prize winning work carried out by George Beadle and
Edward Tatum at Stanford University on the orange breadmould,
Neurospora crassa. Having worked with the Russian geneticist
Boris Ephrussi in Paris in the 1930s on the genetic determina-
tion of eye colour in Drosophila, Beadle became convinced that
genes somehow shape biochemical pathways. He and Tatum now
irradiated Neurospora with X-rays and showed that moulds with
certain defective genes due to radiation could not produce the
enzymes required for the breakdown of the simple elements of
their diet. Garrod studied a naturally occurring genetic defect
in humans, whereas Beadle and Tatum studied an artificially
induced defect in a fungus, but they both reached the same con-
clusion: one gene, one enzyme. This result tended to support the
conclusions reached by J.S. Huxley in his earlier work demon-
strating the action of ‘rate genes’ affecting eye colour in the fresh-
water shrimp, Gammarus, and those of R. Scott-Monscrieff based
on her study of the genetics of flower pigmentation in distinct
strains of snapdragon, Antirrhinums. In the 1950s, the Ameri-
can chemist Linus Pauling perceived that sickle cell anaemia in
humans is caused by a defect in haemoglobin and that the disease
is inherited in simple, Mendelian manner. Pauling thus gener-
alised Garrod’s adage even further, and ‘one gene, one enzyme’
now became one gene, one protein. See also: Beadle, George
Wells; Pauling, Linus Carl; Tatum, Edward Lawrie
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History of Classical Genetics
What Are Genes Made of?
Alongside the investigation of what genes actually do, came the
investigation of what they are made of. Morgan had postulated
the physical existence of genes on the chromosomes, but this
was based on a statistical inference gleaned from the results
of breeding experiments. An early landmark on the road to the
elucidation of the physical nature of the gene was achieved by
Morgan’s former student, Hermann Muller, who in 1927 showed
that genes were actual physical entities by exposing the chromo-
somes of flies to X-rays and observing that the physical changes to
the chromosomes induced by the radiation resulted in mutations
expressed in the phenotype of the flies. Max Delbrück, a physicist
turned geneticist working in Berlin in the mid-1930s, combined
X-ray experimental data and quantum mechanical reasoning to
account for mutations in terms of the chemical and physical
behaviour of atoms. Delbrück moved to the United States in 1937
and began independent collaborations with the Italian refugee
geneticist Salvador Luria and the chemist Alfred Hershey that
resulted in the formation of the Phage Group, an informal net-
work of viral and bacterial geneticists focused on the study of
bacteriophage – a tiny virus that infects bacteria and multiplies
rapidly inside the host. Delbrück the physicist envisioned this
system as the biological analogue to the hydrogen atom: sim-
ple, easy to study and pregnant with information about the nature
of transmission and its material. See also: Cold Spring Har-
bor Laboratory; Delbruck, ̈ Max Ludwig Henning; Hershey,
Alfred Day; History of Bacteriology; History of Molecular
Biology; Muller, Hermann Joseph; Mutagenesis
What genes were actually made of was still unknown. Beadle
and Tatum’s work, because it associated genes with enzymes,
tended to bolster the widely held belief that genes were made
of protein. If they were concentrated in the nucleus, genes could
be either protein or DNA, and chemical analysis had shown that
DNA was a much simpler molecule than protein, hence a lesser
candidate to be the bearer of genetic information. But in 1944,
a group at the Rockefeller Institute for Medical Research led by
Oswald T. Avery reported that it had succeeded in transforming
a non-infectious bacteria into an infectious one, it had carefully
isolated the ‘transforming’ factor, and the factor was DNA. An
older gentleman with a retiring personality, Avery shied away
from pressing the point, and most biologists continued to believe
that genes were made of protein. In 1952, however, Hershey and
Martha Chase, both members of the Phage Group, showed that
when a bacteriophage infects a bacterial cell, it is DNA and DNA
alone that is injected into the bacteria; the protein coat of the virus
invariably remains outside, discarded. This was strong evidence
that DNA was in fact the genetic material. See also: Avery,
Oswald Theodore; Macleod, John James Richard; McCarty,
Maclyn; Nucleic Acids as Genetic Material
During this period, the metaphor of information grew in promi-
nence in biology. The notion of information that was developed
in various guises by the mathematicians Claude Shannon, Alan
Turing, John von Neumann and Norbert Wiener, inspired the
idea that genetic transmission involves the transmission of infor-
mation. This frame of thought was implied already in 1943 by
5
 History of Classical Genetics
the quantum physics pioneer Erwin Schrödinger in his visionary
book What is Life?, but was largely metaphorical.
The real clincher came with the description of the structure of
DNA, a Nobel Prize winning feat accomplished by James Watson
and Francis Crick at Cambridge University in 1953. Watson,
a young American member of the Phage Group, and Crick, a
British physicist struggling to complete a dissertation in biology,
used the X-ray crystallographic photographs taken principally by
Rosalind Franklin at Kings College, London and the biochemist
Erwin Chargaff’s 1:1 nucleotide ratio, together with other chem-
ical and physical assumptions about the molecule, to construct a
tinker-toy double-helical model of DNA in which complemen-
tary nucleotide base pairs – adenine with thymine, cytosine with
guanine – comprise the rungs of a twisting molecular ladder. The
model immediately suggested to Watson and Crick a copying
mechanism that could explain how genetic information is passed
down from generation to generation. When the two strands of the
double helix would separate, two single strings of complimentary
nucleotides would each be able to form a template for the cre-
ation of a new double helix identical to the original. Moreover, the
sequence of nucleotides could be analogous to a sequence of let-
ters in a sentence indicating the sequence of amino acids making
up a protein. What remained was to figure out the code and basic
molecular machinery by which information in the form of DNA
is translated into the amino acids strung together to construct pro-
teins, the basic building blocks of living organisms. See also:
Chargaff, Erwin; History of Molecular Biology; Molecular
Biology: The Central Dogma; Crick, Francis Harry Comp-
ton; Watson, James Dewey
Once this was accomplished principally in the 1960s and
into the 1970s, gene function could now begin to be studied
at the molecular level. The development of the technique of
recombinant DNA in the 1970s, table-top sequence-determining
machines in the 1980s and computerised databases of entire
genetic sequences of different organisms in the 1990s and into
the twenty-first century have been major accomplishments of the
molecular age. Molecular investigations have tended to empha-
sise the role of the mechanisms responsible for the differential
expression in time and in place of genes and the role of genes
in development. The results have complicated some of the earlier
models of classical genetics: the one gene, one enzyme model, for
instance, has had to be modified with the discovery of develop-
mental and structural genes alongside those coding for functional
proteins. The assumptions of classical genetics, however, con-
tinue to underpin the crafts of agricultural breeding and genetic
counselling, whereas molecular genetics has generated the tech-
nology of genetic engineering. Almost 150 years after the pub-
lication of Mendel’s momentous paper on the hybridisation of
peas, genetics is a burgeoning, multidisciplinary field, rich in
promise for understanding heredity, development, evolution and
disease. See also: Genes: Definition and Structure; Genetic
Counselling; History of Physiology
6 eLS © 2015, John Wiley & Sons, Ltd. www.els.net
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References
Allen GE (1978) Thomas Hunt Morgan: The Man and His Science.
Princeton, NJ: Princeton University Press.
Carlson EA (1966) The Gene: A Critical History. Philadelphia,
London: W. B. Saunders.
Carlson EA (2004) Mendel’s Legacy: The Origin of Classical Genet-
ics. Plainview, NY: Cold Spring Harbor Press.
Judson HF (1996) The Eighth Day of Creation: Makers of the Revo-
lution in Biology. Plainview, NY: Cold Spring Harbor Laboratory
Press.
Kay LE (2000) Who Wrote the Book of Life? A History of the Genetic
Code. Stanford, CA: Stanford University Press.
Keller EF (2000) The Century of the Gene. Cambridge, MA: Harvard
University Press.
Kohler R (1994) Lords of the Fly: Drosophila Genetics and the
Experimental Life. Chicago, IL: Chicago University Press.
Müller-Wille S and Rheinberger J-J (2012) A Cultural History of
Heredity. Chicago, IL and London, UK: The University of Chicago
Press.
Olby R (1994) The Path to the Double Helix: The Discovery of DNA.
New York: Dover Publications.
Orel V (1996) Gregor Mendel: The First Geneticist. Oxford, UK:
Oxford University Press.
Schwartz J (2010) In Pursuit of the Gene From Darwin to DNA.
Cambridge, MA: Harvard University Press.
Watson JD (1968) The Double Helix. New York: Atheneum.
Further Reading
Allen GE (1978) Thomas Hunt Morgan: The Man and His Science.
Princeton, NJ: Princeton University Press.
Carlson EA (2004) Mendel’s Legacy: The Origin of Classical Genet-
ics. Plainview, NY: Cold Spring Harbor Press.
Judson HF (1996) The Eighth Day of Creation: Makers of the Revo-
lution in Biology. Plainview, NY: Cold Spring Harbor Laboratory
Press.
Kay LE (2000) Who Wrote the Book of Life? A History of the Genetic
Code. Stanford, CA: Stanford University Press.
Keller EF (2000) The Century of the Gene. Cambridge, MA: Harvard
University Press.
Kohler R (1994) Lords of the Fly: Drosophila Genetics and the
Experimental Life. Chicago, IL: Chicago University Press.
Olby R (1994) The Path to the Double Helix: The Discovery of DNA.
New York, NY: Dover Publications.
Orel V (1996) Gregor Mendel: The First Geneticist. Oxford, UK:
Oxford University Press.
Schwartz J (2010) In Pursuit of the Gene from Darwin to DNA.
Cambridge, MA: Harvard University Press.
Watson JD (1968) The Double Helix. New York, NY: Atheneum.