Charles Darwin's pangenesis theory postulated that every part of the body emits tiny particles called gemmules which migrate to the gonads
and are transferred to offspring. Gemmules were thought to develop into
their associated body parts as offspring matures. The theory implied
that changes to the body during an organism's life would be inherited,
as proposed in Lamarckism.
Pangenesis was Charles Darwin's hypothetical mechanism for heredity, in which he proposed that each part of the body continually emitted its own type of small organic particles called gemmules that aggregated in the gonads, contributing heritable information to the gametes. He presented this 'provisional hypothesis' in his 1868 work The Variation of Animals and Plants Under Domestication,
intending it to fill what he perceived as a major gap in evolutionary
theory at the time. The etymology of the word comes from the Greek words pan (a prefix meaning "whole", "encompassing") and genesis ("birth") or genos ("origin"). Pangenesis mirrored ideas originally formulated by Hippocrates and other pre-Darwinian scientists, but using new concepts such as cell theory,
explaining cell development as beginning with gemmules which were
specified to be necessary for the occurrence of new growths in an
organism, both in initial development and regeneration. It also accounted for regeneration and the Lamarckian
concept of the inheritance of acquired characteristics, as a body part
altered by the environment would produce altered gemmules. This made
Pangenesis popular among the neo-Lamarckian school of evolutionary
thought. This hypothesis was made effectively obsolete after the 1900 rediscovery among biologists of Gregor Mendel's theory of the particulate nature of inheritance.
Early history
Pangenesis was similar to ideas put forth by Hippocrates, Democritus and other pre-Darwinian scientists in proposing that the whole of parental organisms participate in heredity (thus the prefix pan).
Darwin wrote that Hippocrates' pangenesis was "almost identical with
mine—merely a change of terms—and an application of them to classes of
facts necessarily unknown to the old philosopher."
Zirkle demonstrated that the idea of inheritance of acquired
characteristics had become fully accepted by the 16th century and
remained immensely popular through to the time of Lamarck's work, at
which point it began to draw more criticism due to lack of hard
evidence.
He also stated that pangenesis was the only scientific explanation ever
offered for this concept, developing from Hippocrates' belief that "the
semen was derived from the whole body."
In the 13th century, pangenesis was commonly accepted on the principle
that semen was a refined version of food unused by the body, which
eventually translated to 15th and 16th century widespread use of
pangenetic principles in medical literature, especially in gynecology. Later pre-Darwinian important applications of the idea included hypotheses about the origin of the differentiation of races.
A theory put forth by Pierre Louis Maupertuis
in 1745 called for particles from both parents governing the attributes
of the child, although some historians have called his remarks on the
subject cursory and vague.
In 1749, the French naturalist Georges-Louis Leclerc, Comte de Buffon
developed a hypothetical system of heredity much like Darwin's
pangenesis, wherein 'organic molecules' were transferred to offspring
during reproduction and stored in the body during development. Commenting on Buffon's views, Darwin stated, "If Buffon had assumed
that his organic molecules had been formed by each separate unit
throughout the body, his view and mine would have been very closely
similar."
In 1801, Erasmus Darwin advocated a hypothesis of pangenesis in the third edition of his book Zoonomia. In 1809, Jean-Baptiste Lamarck in his Philosophie Zoologique
put forth evidence for the idea that characteristics acquired during
the lifetime of an organism, from either environmental or behavioural
effects, may be passed on to the offspring. Charles Darwin first had
significant contact with Lamarckism during his time at the University of Edinburgh Medical School in the late 1820s, both through Robert Edmond Grant, whom he assisted in research, and in Erasmus's journals.
Darwin's first known writings on the topic of Lamarckian ideas as they
related to inheritance are found in a notebook he opened in 1837, also
entitled Zoonomia. Historian Jonathan Hodge states that the theory of pangenesis itself first appeared in Darwin's notebooks in 1841.
In 1861, the Irish physician Henry Freke developed a variant of pangenesis in his book Origin of Species by Means of Organic Affinity. Freke proposed that all life was developed from microscopic organic agents which he named granules, which existed as 'distinct species of organizing matter' and would develop into different biological structures.
Four years before the publication of Variation, in his 1864 book Principles of Biology, Herbert Spencer
proposed a theory of "physiological units" similar to Darwin's
gemmules, which likewise were said to be related to specific body parts
and responsible for the transmission of characteristics of those body
parts to offspring. He supported the Lamarckian idea of transmission of acquired characteristics.
Darwin had debated whether to publish a theory of heredity for an
extended period of time due to its highly speculative nature. He
decided to include pangenesis in Variation after sending a 30-page manuscript to his close friend and supporter Thomas Huxley in May 1865, which was met by significant criticism from Huxley that made Darwin even more hesitant.
However, Huxley eventually advised Darwin to publish, writing:
"Somebody rummaging among your papers half a century hence will find
Pangenesis & say 'See this wonderful anticipation of our modern
Theories—and that stupid ass, Huxley, prevented his publishing them'" Darwin's initial version of pangenesis appeared in the first edition of Variation in 1868, and was later reworked for the publication of a second edition in 1875.
Theory
Darwin
Darwin's pangenesis theory attempted to explain the process of sexual reproduction, inheritance of traits, and complex developmental phenomena such as cellular regeneration in a unified mechanistic structure. Longshan Liu wrote that in modern terms, pangenesis deals with issues of "dominance inheritance, graft hybridization, reversion, xenia, telegony,
the inheritance of acquired characters, regeneration and many groups of
facts pertaining to variation, inheritance and development."
Mechanistically, Darwin proposed pangenesis to occur through the
transfer of organic particles which he named 'gemmules.' Gemmules, which
he also sometimes referred to as plastitudes, pangenes, granules,
or germs, were supposed to be shed by the organs of the body and
carried in the bloodstream to the reproductive organs where they
accumulated in the germ cells or gametes. Their accumulation was thought to occur by some sort of a 'mutual affinity.'
Each gemmule was said to be specifically related to a certain body
part- as described, they did not contain information about the entire
organism.
The different types were assumed to be dispersed through the whole
body, and capable of self-replication given 'proper nutriment'. When
passed on to offspring via the reproductive process, gemmules were
thought to be responsible for developing into each part of an organism
and expressing characteristics inherited from both parents.
Darwin thought this to occur in a literal sense: he explained cell
proliferation to progress as gemmules to bind to more developed cells of
their same character and mature. In this sense, the uniqueness of each
individual would be due to their unique mixture of their parents'
gemmules, and therefore characters. Similarity to one parent over the other could be explained by a quantitative superiority of one parent's gemmules.
Yongshen Lu points out that Darwin knew of cells' ability to multiply
by self-division, so it is unclear how Darwin supposed the two
proliferation mechanisms to relate to each other.
He did clarify in a later statement that he had always supposed
gemmules to only bind to and proliferate from developing cells, not
mature ones. Darwin hypothesized that gemmules might be able to survive and multiply outside of the body in a letter to J. D. Hooker in 1870.
Some gemmules were thought to remain dormant for generations,
whereas others were routinely expressed by all offspring. Every child
was built up from selective expression of the mixture of the parents and
grandparents' gemmules coming from either side. Darwin likened this to
gardening: a flowerbed could be sprinkled with seeds "most of which soon
germinate, some lie for a period dormant, whilst others perish." He did not claim gemmules were in the blood, although his theory was often interpreted in this way. Responding to Fleming Jenkin's review of On the Origin of Species,
he argued that pangenesis would permit the preservation of some
favourable variations in a population so that they wouldn't die out
through blending.
Darwin thought that environmental effects that caused altered
characteristics would lead to altered gemmules for the affected body
part. The altered gemmules would then have a chance of being transferred
to offspring, since they were assumed to be produced throughout an
organism's life.
Thus, pangenesis theory allowed for the Lamarckian idea of transmission
of characteristics acquired through use and disuse. Accidental gemmule
development in incorrect parts of the body could explain deformations
and the 'monstrosities' Darwin cited in Variation.
De Vries
Hugo de Vries characterized his own version of pangenesis theory in his 1889 book Intracellular Pangenesis with two propositions, of which he only accepted the first:
I. In the cells there are numberless particles which differ from
each other, and represent the individual cells, organs, functions and
qualities of the whole individual. These particles are much larger than
the chemical molecules and smaller than the smallest known organisms;
yet they are for the most part comparable to the latter, because, like
them, they can divide and multiply through nutrition and growth. They
are transmitted, during cell-division, to the daughter-cells: this is
the ordinary process of heredity.
II. In addition to this, the cells of the organism, at every stage
of development, throw off such particles, which are conducted to the
germ-cells and transmit to them those characters which the respective
cells may have acquired during development.
Other variants
The historian of science Janet Browne points out that while Spencer and Carl von Nägeli
also put forth ideas for systems of inheritance involving gemmules,
their version of gemmules differed from Darwin's in that it contained "a
complete microscopic blueprint for an entire creature." Spencer published his theory of "physiological units" three years prior to Darwin's publication of Variation.
Browne adds that Darwin believed specifically in gemmules from each
body part because they might explain how environmental effects could be
passed on as characteristics to offspring.
Interpretations and applications of pangenesis continued to appear frequently in medical literature up until Weismann's experiments and subsequent publication on germ-plasm theory in 1892.
For instance, an address by Huxley spurred on substantial work by Dr.
James Ross in linking ideas found in Darwin's pangenesis to the germ theory of disease. Ross cites the work of both Darwin and Spencer as key to his application of pangenetic theory.
Collapse
Galton's experiments on rabbits
Darwin's half-cousin Francis Galton
conducted wide-ranging inquiries into heredity which led him to refute
Charles Darwin's hypothetical theory of pangenesis. In consultation with
Darwin, he set out to see if gemmules were transported in the blood. In
a long series of experiments from 1869 to 1871, he transfused the blood
between dissimilar breeds of rabbits, and examined the features of
their offspring. He found no evidence of characters transmitted in the
transfused blood.
Galton was troubled because he began the work in good faith, intending to prove Darwin right, and having praised pangenesis in Hereditary Genius
in 1869. Cautiously, he criticized his cousin's theory, although
qualifying his remarks by saying that Darwin's gemmules, which he called
"pangenes", might be temporary inhabitants of the blood that his
experiments had failed to pick up.
Darwin challenged the validity of Galton's experiment, giving his reasons in an article published in Nature where he wrote:
Now, in the chapter on Pangenesis in my Variation of Animals and Plants under Domestication,
I have not said one word about the blood, or about any fluid proper to
any circulating system. It is, indeed, obvious that the presence of
gemmules in the blood can form no necessary part of my hypothesis; for I
refer in illustration of it to the lowest animals, such as the
Protozoa, which do not possess blood or any vessels; and I refer to
plants in which the fluid, when present in the vessels, cannot be
considered as true blood." He goes on to admit: "Nevertheless, when I
first heard of Mr. Galton's experiments, I did not sufficiently reflect
on the subject, and saw not the difficulty of believing in the presence
of gemmules in the blood.
After the circulation of Galton's results, the perception of
pangenesis quickly changed to severe skepticism if not outright
disbelief.
Weismann
August Weismann's germ plasm
theory. The hereditary material, the germ plasm, is confined to the
gonads. Somatic cells (of the body) develop afresh in each generation
from the germ plasm. The implied Weismann barrier between the germ line and the soma prevents Lamarckian inheritance.
August Weismann's idea, set out in his 1892 book Das Keimplasma: eine Theorie der Vererbung (The Germ Plasm: a Theory of Inheritance), was that the hereditary material, which he called the germ plasm, and the rest of the body (the soma)
had a one-way relationship: the germ-plasm formed the body, but the
body did not influence the germ-plasm, except indirectly in its
participation in a population subject to natural selection. This
distinction is commonly referred to as the Weismann Barrier.
If correct, this made Darwin's pangenesis wrong and Lamarckian
inheritance impossible. His experiment on mice, cutting off their tails
and showing that their offspring had normal tails across multiple
generations, was proposed as a proof of the non-existence of Lamarckian
inheritance, although Peter Gauthier has argued that Weismann's experiment showed only that injury did not affect the germ plasm and neglected to test the effect of Lamarckian use and disuse. Weismann argued strongly and dogmatically for Darwinism and against neo-Lamarckism, polarising opinions among other scientists. This increased anti-Darwinian feeling, contributing to its eclipse.
After pangenesis
Darwin's pangenesis theory was widely criticised, in part for its Lamarckian premise that parents could pass on traits acquired in their lifetime. Conversely, the neo-Lamarckians of the time seized upon pangenesis as evidence to support their case.
Italian Botanist Federico Delpino's objection that gemmules' ability to
self-divide is contrary to their supposedly innate nature gained
considerable traction; however, Darwin was dismissive of this criticism,
remarking that the particulate agents of smallpox and scarlet fever
seem to have such characteristics. Lamarckism fell from favour after August Weismann's
research in the 1880s indicated that changes from use (such as lifting
weights to increase muscle mass) and disuse (such as being lazy and
becoming weak) were not heritable.
However, some scientists continued to voice their support in spite of
Galton's and Weismann's results: notably, in 1900 Karl Pearson wrote
that pangenesis "is no more disproved by the statement that 'gemmules
have not been found in the blood,' than the atomic theory is disproved
by the fact that no atoms have been found in the air." Finally, the rediscovery of Mendel's Laws of Inheritance in 1900 led to pangenesis being fully set aside. Julian Huxley has observed that the later discovery of chromosomes and the research of T. H. Morgan also made pangenesis untenable.
Some of Darwin's pangenesis principles do relate to heritable aspects of phenotypic plasticity,
although the status of gemmules as a distinct class of organic
particles has been firmly rejected. However, starting in the 1950s, many
research groups in revisiting Galton's experiments found that heritable
characteristics could indeed arise in rabbits and chickens following
DNA injection or blood transfusion.
This type of research originated in the Soviet Union in the late 1940s
in the work of Sopikov and others, and was later corroborated by
researchers in Switzerland as it was being further developed by the
Soviet scientists.Notably, this work was supported in the USSR in part due to its conformation with the ideas of Trofim Lysenko, who espoused a version of neo-Lamarckism as part of Lysenkoism. Further research of this heritability of acquired characteristics developed into, in part, the modern field of epigenetics.
Darwin himself had noted that "the existence of free gemmules is a
gratuitous assumption"; by some accounts in modern interpretation,
gemmules may be considered a prescient mix of DNA, RNA, proteins,
prions, and other mobile elements that are heritable in a non-Mendelian
manner at the molecular level. Liu points out that Darwin's ideas about gemmules replicating outside of the body are predictive of in vitro gene replication used, for instance, in PCR.
Lamarck argued, as part of his theory of heredity, that a blacksmith's sons inherit the strong muscles he acquires from his work.
Lamarckism, also known as Lamarckian inheritance or neo-Lamarckism, is the notion that an organism can pass on to its offspring physical characteristics that the parent organism acquired through use or disuse during its lifetime. It is also called the inheritance of acquired characteristics or more recently soft inheritance. The idea is named after the French zoologistJean-Baptiste Lamarck (1744–1829), who incorporated the classical era theory of soft inheritance into his theory of evolution as a supplement to his concept of orthogenesis, a drive towards complexity.
Introductory textbooks contrast Lamarckism with Charles Darwin's theory of evolution by natural selection. However, Darwin's book On the Origin of Species gave credence to the idea of heritable effects of use and disuse, as Lamarck had done, and his own concept of pangenesis similarly implied soft inheritance.
Many researchers from the 1860s onwards attempted to find
evidence for Lamarckian inheritance, but these have all been explained
away, either by other mechanisms such as genetic contamination or as fraud. August Weismann's
experiment, considered definitive in its time, is now considered to
have failed to disprove Lamarckism, as it did not address use and
disuse. Later, Mendelian genetics supplanted the notion of inheritance of acquired traits, eventually leading to the development of the modern synthesis, and the general abandonment of Lamarckism in biology. Despite this, interest in Lamarckism has continued.
Since c. 2000 new experimental results in the fields of epigenetics, genetics, and somatic hypermutation proved the possibility of transgenerational epigenetic inheritance of traits acquired by the previous generation. These proved a limited validity of Lamarckism. The inheritance of the hologenome,
consisting of the genomes of all an organism's symbiotic microbes as
well as its own genome, is also somewhat Lamarckian in effect, though
entirely Darwinian in its mechanisms.
Early history
Origins
Jean-Baptiste Lamarck repeated the ancient folk wisdom of the inheritance of acquired characteristics.
The inheritance of acquired characteristics was proposed in ancient
times and remained a current idea for many centuries. The historian of
science Conway Zirkle wrote in 1935 that:
Lamarck was neither the first nor
the most distinguished biologist to believe in the inheritance of
acquired characters. He merely endorsed a belief which had been
generally accepted for at least 2,200 years before his time and used it
to explain how evolution could have taken place. The inheritance of
acquired characters had been accepted previously by Hippocrates, Aristotle, Galen, Roger Bacon, Jerome Cardan, Levinus Lemnius, John Ray, Michael Adanson, Jo. Fried. Blumenbach and Erasmus Darwin among others.
Zirkle noted that Hippocrates described pangenesis,
the theory that what is inherited derives from the whole body of the
parent, whereas Aristotle thought it impossible; but that all the same,
Aristotle implicitly agreed to the inheritance of acquired
characteristics, giving the example of the inheritance of a scar, or of
blindness, though noting that children do not always resemble their
parents. Zirkle recorded that Pliny the Elder
thought much the same. Zirkle pointed out that stories involving the
idea of inheritance of acquired characteristics appear numerous times in
ancient mythology and the Bible and persisted through to Rudyard Kipling's Just So Stories. The idea is mentioned in 18th century sources such as Diderot's D'Alembert's Dream. Erasmus Darwin's Zoonomia (c. 1795) suggested that warm-bloodedanimals
develop from "one living filament... with the power of acquiring new
parts" in response to stimuli, with each round of "improvements" being
inherited by successive generations.
Charles Darwin's pangenesis theory. Every part of the body emits tiny gemmules which migrate to the gonads
and contribute to the next generation via the fertilised egg. Changes
to the body during an organism's life would be inherited, as in
Lamarckism.
Charles Darwin's On the Origin of Species
proposed natural selection as the main mechanism for development of
species, but (like Lamarck) gave credence to the idea of heritable
effects of use and disuse as a supplementary mechanism. Darwin subsequently set out his concept of pangenesis in the final chapter of his book The Variation of Animals and Plants Under Domestication
(1868), which gave numerous examples to demonstrate what he thought was
the inheritance of acquired characteristics. Pangenesis, which he
emphasised was a hypothesis, was based on the idea that somatic cells would, in response to environmental stimulation (use and disuse), throw off 'gemmules' or 'pangenes' which travelled around the body, though not necessarily in the bloodstream.
These pangenes were microscopic particles that supposedly contained
information about the characteristics of their parent cell, and Darwin
believed that they eventually accumulated in the germ cells where they could pass on to the next generation the newly acquired characteristics of the parents.
Darwin's half-cousin, Francis Galton, carried out experiments on rabbits, with Darwin's cooperation, in which he transfused the blood
of one variety of rabbit into another variety in the expectation that
its offspring would show some characteristics of the first. They did
not, and Galton declared that he had disproved Darwin's hypothesis of
pangenesis, but Darwin objected, in a letter to the scientific journal Nature,
that he had done nothing of the sort, since he had never mentioned
blood in his writings. He pointed out that he regarded pangenesis as
occurring in protozoa and plants, which have no blood, as well as in animals.
Lamarck's evolutionary framework
Lamarck's two-factor theory involves 1) a complexifying force that drives animal body plans towards higher levels (orthogenesis) creating a ladder of phyla,
and 2) an adaptive force that causes animals with a given body plan to
adapt to circumstances (use and disuse, inheritance of acquired
characteristics), creating a diversity of species and genera. Lamarckism is the name now widely used for the adaptive force.
Between 1800 and 1830, Lamarck proposed a systematic theoretical
framework for understanding evolution. He saw evolution as comprising
four laws:
"Life by its own force, tends to increase the volume of all
organs which possess the force of life, and the force of life extends
the dimensions of those parts up to an extent that those parts bring to
themselves;"
"The production of a new organ in an animal body, results from a new
requirement arising. and which continues to make itself felt, and a new
movement which that requirement gives birth to, and its
upkeep/maintenance;"
"The development of the organs, and their ability, are constantly a result of the use of those organs."
"All that has been acquired, traced, or changed, in the physiology
of individuals, during their life, is conserved through the genesis,
reproduction, and transmitted to new individuals who are related to
those who have undergone those changes."
Lamarck's discussion of heredity
In
1830, in an aside from his evolutionary framework, Lamarck briefly
mentioned two traditional ideas in his discussion of heredity, in his
day considered to be generally true. The first was the idea of use
versus disuse; he theorized that individuals lose characteristics they
do not require, or use, and develop characteristics that are useful. The
second was to argue that the acquired traits were heritable. He gave as
an imagined illustration the idea that when giraffes
stretch their necks to reach leaves high in trees, they would
strengthen and gradually lengthen their necks. These giraffes would then
have offspring with slightly longer necks. In the same way, he argued, a
blacksmith,
through his work, strengthens the muscles in his arms, and thus his
sons would have similar muscular development when they mature. Lamarck
stated the following two laws:
Première Loi: Dans tout animal qui n' a point dépassé le
terme de ses développemens, l' emploi plus fréquent et soutenu d' un
organe quelconque, fortifie peu à peu cet organe, le développe, l'
agrandit, et lui donne une puissance proportionnée à la durée de cet
emploi; tandis que le défaut constant d' usage de tel organe,
l'affoiblit insensiblement, le détériore, diminue progressivement ses
facultés, et finit par le faire disparoître.
Deuxième Loi: Tout ce que la nature a fait acquérir ou perdre aux
individus par l' influence des circonstances où leur race se trouve
depuis long-temps exposée, et, par conséquent, par l' influence de l'
emploi prédominant de tel organe, ou par celle d' un défaut constant d'
usage de telle partie; elle le conserve par la génération aux nouveaux
individus qui en proviennent, pourvu que les changemens acquis soient
communs aux deux sexes, ou à ceux qui ont produit ces nouveaux
individus.
English translation:
First Law [Use and Disuse]: In every animal which has not passed
the limit of its development, a more frequent and continuous use of any
organ gradually strengthens, develops and enlarges that organ, and
gives it a power proportional to the length of time it has been so used;
while the permanent disuse of any organ imperceptibly weakens and
deteriorates it, and progressively diminishes its functional capacity,
until it finally disappears.
Second Law [Soft Inheritance]: All the acquisitions or losses
wrought by nature on individuals, through the influence of the
environment in which their race has long been placed, and hence through
the influence of the predominant use or permanent disuse of any organ;
all these are preserved by reproduction to the new individuals which
arise, provided that the acquired modifications are common to both
sexes, or at least to the individuals which produce the young.
In essence, a change in the environment brings about change in "needs" (besoins),
resulting in change in behaviour, causing change in organ usage and
development, bringing change in form over time—and thus the gradual transmutation of the species. As the evolutionary biologists and historians of science Conway Zirkle, Michael Ghiselin, and Stephen Jay Gould have pointed out, these ideas were not original to Lamarck.
Weismann's experiment
August Weismann's germ plasm theory. The hereditary material, the germ plasm, is confined to the gonads and the gametes. Somatic cells (of the body) develop afresh in each generation from the germ plasm, creating an invisible "Weismann barrier" to Lamarckian influence from the soma to the next generation.
August Weismann's germ plasm theory held that germline cells in the gonads
contain information that passes from one generation to the next,
unaffected by experience, and independent of the somatic (body) cells.
This implied what came to be known as the Weismann barrier, as it would make Lamarckian inheritance from changes to the body difficult or impossible.
Weismann conducted the experiment of removing the tails of 68 white mice,
and those of their offspring over five generations, and reporting that
no mice were born in consequence without a tail or even with a shorter
tail. In 1889, he stated that "901 young were produced by five
generations of artificially mutilated parents, and yet there was not a
single example of a rudimentary tail or of any other abnormality in this
organ." The experiment, and the theory behind it, were thought at the time to be a refutation of Lamarckism.
The experiment's effectiveness in refuting Lamarck's hypothesis is doubtful, as it did not address the use and disuse of characteristics in response to the environment. The biologist Peter Gauthier noted in 1990 that:
Can Weismann's experiment be
considered a case of disuse? Lamarck proposed that when an organ was not
used, it slowly, and very gradually atrophied. In time, over the course
of many generations, it would gradually disappear as it was inherited
in its modified form in each successive generation. Cutting the tails
off mice does not seem to meet the qualifications of disuse, but rather
falls in a category of accidental misuse... Lamarck's hypothesis has
never been proven experimentally and there is no known mechanism to
support the idea that somatic change, however acquired, can in some way
induce a change in the germplasm. On the other hand it is difficult to
disprove Lamarck's idea experimentally, and it seems that Weismann's
experiment fails to provide the evidence to deny the Lamarckian
hypothesis, since it lacks a key factor, namely the willful exertion of
the animal in overcoming environmental obstacles.
Ghiselin also considered the Weismann tail-chopping experiment to
have no bearing on the Lamarckian hypothesis, writing in 1994 that:
The acquired characteristics that figured in Lamarck's
thinking were changes that resulted from an individual's own drives and
actions, not from the actions of external agents. Lamarck was not
concerned with wounds, injuries or mutilations, and nothing that Lamarck
had set forth was tested or "disproven" by the Weismann tail-chopping
experiment.
The historian of science Rasmus Winther stated that Weismann had
nuanced views about the role of the environment on the germ plasm.
Indeed, like Darwin, he consistently insisted that a variable
environment was necessary to cause variation in the hereditary material.
Textbook Lamarckism
The long neck of the giraffe
is often used as an example in popular explanations of Lamarckism.
However, this was only a small part of his theory of evolution towards
"perfection"; it was a hypothetical illustration; and he used it to
discuss his theory of heredity, not evolution.
The identification of Lamarckism with the inheritance of acquired
characteristics is regarded by evolutionary biologists including
Ghiselin as a falsified artifact of the subsequent history of
evolutionary thought, repeated in textbooks without analysis, and
wrongly contrasted with a falsified picture of Darwin's thinking.
Ghiselin notes that "Darwin accepted the inheritance of acquired
characteristics, just as Lamarck did, and Darwin even thought that there
was some experimental evidence to support it."
Gould wrote that in the late 19th century, evolutionists "re-read
Lamarck, cast aside the guts of it ... and elevated one aspect of the
mechanics—inheritance of acquired characters—to a central focus it never
had for Lamarck himself."
He argued that "the restriction of 'Lamarckism' to this relatively
small and non-distinctive corner of Lamarck's thought must be labelled
as more than a misnomer, and truly a discredit to the memory of a man
and his much more comprehensive system."
The period of the history of evolutionary thought between Darwin's death in the 1880s, and the foundation of population genetics in the 1920s and the beginnings of the modern evolutionary synthesis in the 1930s, is called the eclipse of Darwinism
by some historians of science. During that time many scientists and
philosophers accepted the reality of evolution but doubted whether
natural selection was the main evolutionary mechanism.
Among the most popular alternatives were theories involving the
inheritance of characteristics acquired during an organism's lifetime.
Scientists who felt that such Lamarckian mechanisms were the key to
evolution were called neo-Lamarckians. They included the British botanistGeorge Henslow
(1835–1925), who studied the effects of environmental stress on the
growth of plants, in the belief that such environmentally-induced
variation might explain much of plant evolution, and the American entomologist Alpheus Spring Packard Jr., who studied blind animals living in caves and wrote a book in 1901 about Lamarck and his work. Also included were paleontologists like Edward Drinker Cope and Alpheus Hyatt,
who observed that the fossil record showed orderly, almost linear,
patterns of development that they felt were better explained by
Lamarckian mechanisms than by natural selection. Some people, including
Cope and the Darwin critic Samuel Butler,
felt that inheritance of acquired characteristics would let organisms
shape their own evolution, since organisms that acquired new habits
would change the use patterns of their organs, which would kick-start
Lamarckian evolution. They considered this philosophically superior to
Darwin's mechanism of random variation acted on by selective pressures.
Lamarckism also appealed to those, like the philosopher Herbert Spencer and the German anatomist Ernst Haeckel, who saw evolution as an inherently progressive process. The German zoologistTheodor Eimer combined Larmarckism with ideas about orthogenesis, the idea that evolution is directed towards a goal.
With the development of the modern synthesis
of the theory of evolution, and a lack of evidence for a mechanism for
acquiring and passing on new characteristics, or even their
heritability, Lamarckism largely fell from favour. Unlike neo-Darwinism,
neo-Lamarckism is a loose grouping of largely heterodox theories and
mechanisms that emerged after Lamarck's time, rather than a coherent
body of theoretical work.
Neo-Lamarckian versions of evolution were widespread in the late 19th
century. The idea that living things could to some degree choose the
characteristics that would be inherited allowed them to be in charge of
their own destiny as opposed to the Darwinian view, which placed them at
the mercy of the environment. Such ideas were more popular than natural
selection in the late 19th century as it made it possible for
biological evolution to fit into a framework of a divine or naturally
willed plan, thus the neo-Lamarckian view of evolution was often
advocated by proponents of orthogenesis. According to the historian of science Peter J. Bowler, writing in 2003:
One of the most emotionally
compelling arguments used by the neo-Lamarckians of the late nineteenth
century was the claim that Darwinism was a mechanistic theory which
reduced living things to puppets driven by heredity. The selection
theory made life into a game of Russian roulette, where life or death
was predetermined by the genes one inherited. The individual could do
nothing to mitigate bad heredity. Lamarckism, in contrast, allowed the
individual to choose a new habit when faced with an environmental
challenge and shape the whole future course of evolution.
Scientists from the 1860s onwards conducted numerous experiments
that purported to show Lamarckian inheritance. Some examples are
described in the table.
19th century experiments attempting to demonstrate Lamarckian inheritance
Paul Kammerer claimed in the 1920s to have found evidence for Lamarckian inheritance in midwife toads, in a case celebrated by the journalist Arthur Koestler, but the results are thought to be either fraudulent or at best misinterpreted.
A century after Lamarck, scientists and philosophers continued to
seek mechanisms and evidence for the inheritance of acquired
characteristics. Experiments were sometimes reported as successful, but
from the beginning these were either criticised on scientific grounds or
shown to be fakes. For instance, in 1906, the philosopher Eugenio Rignano argued for a version that he called "centro-epigenesis", but it was rejected by most scientists. Some of the experimental approaches are described in the table.
Early 20th century experiments attempting to demonstrate Lamarckian inheritance
Criticised by William Bateson; Tower claimed all results lost in fire; William E. Castle visited laboratory, found fire suspicious, doubted claim that steam leak had killed all beetles, concluded faked data.
The British anthropologist Frederic Wood Jones and the South African paleontologist Robert Broom supported a neo-Lamarckian view of human evolution. The German anthropologist Hermann Klaatsch relied on a neo-Lamarckian model of evolution to try and explain the origin of bipedalism.
Neo-Lamarckism remained influential in biology until the 1940s when the
role of natural selection was reasserted in evolution as part of the
modern evolutionary synthesis.
Herbert Graham Cannon, a British zoologist, defended Lamarckism in his 1959 book Lamarck and Modern Genetics. In the 1960s, "biochemical Lamarckism" was advocated by the embryologist Paul Wintrebert.
In 1987, Ryuichi Matsuda coined the term "pan-environmentalism" for his evolutionary theory which he saw as a fusion of Darwinism with neo-Lamarckism. He held that heterochrony is a main mechanism for evolutionary change and that novelty in evolution can be generated by genetic assimilation. His views were criticized by Arthur M. Shapiro
for providing no solid evidence for his theory. Shapiro noted that
"Matsuda himself accepts too much at face value and is prone to
wish-fulfilling interpretation."
A form of Lamarckism was revived in the Soviet Union of the 1930s when Trofim Lysenko promoted the ideologically driven research programme, Lysenkoism; this suited the ideological opposition of Joseph Stalin to genetics.
Lysenkoism influenced Soviet agricultural policy which in turn was
later blamed for the numerous massive crop failures experienced within
Soviet states.
Critique
George Gaylord Simpson in his book Tempo and Mode in Evolution (1944) claimed that experiments in heredity have failed to corroborate any Lamarckian process.
Simpson noted that neo-Lamarckism "stresses a factor that Lamarck
rejected: inheritance of direct effects of the environment" and
neo-Lamarckism is closer to Darwin's pangenesis than Lamarck's views.
Simpson wrote, "the inheritance of acquired characters, failed to meet
the tests of observation and has been almost universally discarded by
biologists."
What Lamarck really did was to accept the hypothesis that
acquired characters were heritable, a notion which had been held almost
universally for well over two thousand years and which his
contemporaries accepted as a matter of course, and to assume that the
results of such inheritance were cumulative from generation to
generation, thus producing, in time, new species. His individual
contribution to biological theory consisted in his application to the
problem of the origin of species of the view that acquired characters
were inherited and in showing that evolution could be inferred logically
from the accepted biological hypotheses. He would doubtless have been
greatly astonished to learn that a belief in the inheritance of acquired
characters is now labeled "Lamarckian," although he would almost
certainly have felt flattered if evolution itself had been so
designated.
Peter Medawar
wrote regarding Lamarckism, "very few professional biologists believe
that anything of the kind occurs—or can occur—but the notion persists
for a variety of nonscientific reasons." Medawar stated there is no
known mechanism by which an adaptation acquired in an individual's
lifetime can be imprinted on the genome and Lamarckian inheritance is
not valid unless it excludes the possibility of natural selection, but
this has not been demonstrated in any experiment.
A host of experiments have been designed to test
Lamarckianism. All that have been verified have proved negative. On the
other hand, tens of thousands of experiments— reported in the journals
and carefully checked and rechecked by geneticists throughout the world—
have established the correctness of the gene-mutation theory beyond all
reasonable doubt... In spite of the rapidly increasing evidence for
natural selection, Lamarck has never ceased to have loyal followers....
There is indeed a strong emotional appeal in the thought that every
little effort an animal puts forth is somehow transmitted to his
progeny.
According to Ernst Mayr, any Lamarckian theory involving the inheritance of acquired characters has been refuted as "DNA
does not directly participate in the making of the phenotype and that
the phenotype, in turn, does not control the composition of the DNA."
Peter J. Bowler has written that although many early scientists took
Lamarckism seriously, it was discredited by genetics in the early
twentieth century.
Mechanisms resembling Lamarckism
Studies in the field of epigenetics, genetics and somatic hypermutation have highlighted the possible inheritance of traits acquired by the previous generation.However, the characterization of these findings as Lamarckism has been disputed.
Transgenerational epigenetic inheritance
DNA molecule with epigenetic marks, created by methylation, enabling a neo-Lamarckian pattern of inheritance for some generations
Epigenetic inheritance has been argued by scientists including Eva Jablonka and Marion J. Lamb to be Lamarckian. Epigenetics is based on hereditary elements other than genes that pass into the germ cells. These include methylation patterns in DNA and chromatin marks on histone proteins, both involved in gene regulation. These marks are responsive to environmental stimuli, differentially affect gene expression, and are adaptive, with phenotypic
effects that persist for some generations. The mechanism may also
enable the inheritance of behavioral traits, for example in chickens, rats
and human populations that have experienced starvation, DNA methylation
resulting in altered gene function in both the starved population and
their offspring. Methylation similarly mediates epigenetic inheritance in plants such as rice. Small RNA molecules, too, may mediate inherited resistance to infection. Handel and Ramagopalan commented that "epigenetics allows the peaceful co-existence of Darwinian and Lamarckian evolution."
Joseph Springer and Dennis Holley commented in 2013 that:
Lamarck and his ideas were ridiculed and discredited. In a
strange twist of fate, Lamarck may have the last laugh. Epigenetics, an
emerging field of genetics, has shown that Lamarck may have been at
least partially correct all along. It seems that reversible and
heritable changes can occur without a change in DNA sequence (genotype)
and that such changes may be induced spontaneously or in response to
environmental factors—Lamarck's "acquired traits." Determining which
observed phenotypes are genetically inherited and which are
environmentally induced remains an important and ongoing part of the
study of genetics, developmental biology, and medicine.
The prokaryoticCRISPR system and Piwi-interacting RNA could be classified as Lamarckian, within a Darwinian framework.
However, the significance of epigenetics in evolution is uncertain. Critics such as the evolutionary biologist Jerry Coyne point out that epigenetic inheritance lasts for only a few generations, so it is not a stable basis for evolutionary change.
The evolutionary biologist T. Ryan Gregory
contends that epigenetic inheritance should not be considered
Lamarckian. According to Gregory, Lamarck did not claim that the
environment directly affected living things. Instead, Lamarck "argued
that the environment created needs to which organisms responded by using
some features more and others less, that this resulted in those
features being accentuated or attenuated, and that this difference was
then inherited by offspring." Gregory has stated that Lamarckian
evolution in epigenetics is more like Darwin's point of view than
Lamarck's.
In 2007, David Haig
wrote that research into epigenetic processes does allow a Lamarckian
element in evolution but the processes do not challenge the main tenets
of the modern evolutionary synthesis as modern Lamarckians have claimed.
Haig argued for the primacy of DNA and evolution of epigenetic switches
by natural selection.
Haig has written that there is a "visceral attraction" to Lamarckian
evolution from the public and some scientists, as it posits the world
with a meaning, in which organisms can shape their own evolutionary
destiny.
Thomas Dickens and Qazi Rahman (2012) have argued that epigenetic
mechanisms such as DNA methylation and histone modification are
genetically inherited under the control of natural selection and do not
challenge the modern synthesis. They dispute the claims of Jablonka and
Lamb on Lamarckian epigenetic processes.
In 2015, Khursheed Iqbal and colleagues discovered that although
"endocrine disruptors exert direct epigenetic effects in the exposed
fetal germ cells, these are corrected by reprogramming events in the
next generation."
Also in 2015, Adam Weiss argued that bringing back Lamarck in the
context of epigenetics is misleading, commenting, "We should remember
[Lamarck] for the good he contributed to science, not for things that
resemble his theory only superficially. Indeed, thinking of CRISPR and
other phenomena as Lamarckian only obscures the simple and elegant way
evolution really works."
Somatic hypermutation and reverse transcription to germline
In the 1970s, the Australian immunologist Edward J. Steele developed a neo-Lamarckian theory of somatic hypermutation within the immune system and coupled it to the reverse transcription of RNA derived from body cells to the DNA of germline
cells. This reverse transcription process supposedly enabled
characteristics or bodily changes acquired during a lifetime to be
written back into the DNA and passed on to subsequent generations.
The mechanism was meant to explain why homologous DNA sequences from the VDJ gene
regions of parent mice were found in their germ cells and seemed to
persist in the offspring for a few generations. The mechanism involved
the somatic selection and clonal amplification of newly acquired antibodygene sequences generated via somatic hypermutation in B-cells. The messenger RNA products of these somatically novel genes were captured by retrovirusesendogenous
to the B-cells and were then transported through the bloodstream where
they could breach the Weismann or soma-germ barrier and reverse
transcribe the newly acquired genes into the cells of the germ line, in
the manner of Darwin's pangenes.
The historian of biology Peter J. Bowler
noted in 1989 that other scientists had been unable to reproduce his
results, and described the scientific consensus at the time:
There is no feedback of information
from the proteins to the DNA, and hence no route by which
characteristics acquired in the body can be passed on through the genes.
The work of Ted Steele (1979) provoked a flurry of interest in the
possibility that there might, after all, be ways in which this reverse
flow of information could take place. ... [His] mechanism did not, in
fact, violate the principles of molecular biology, but most biologists
were suspicious of Steele's claims, and attempts to reproduce his
results have failed.
Bowler commented that "[Steele's] work was bitterly criticized at the
time by biologists who doubted his experimental results and rejected
his hypothetical mechanism as implausible."
The hologenome theory of evolution, while Darwinian, has Lamarckian aspects. An individual animal or plant lives in symbiosis with many microorganisms, and together they have a "hologenome" consisting of all their genomes. The hologenome can vary like any other genome by mutation, sexual recombination, and chromosome rearrangement,
but in addition it can vary when populations of microorganisms increase
or decrease (resembling Lamarckian use and disuse), and when it gains
new kinds of microorganism (resembling Lamarckian inheritance of
acquired characteristics). These changes are then passed on to
offspring.
The mechanism is largely uncontroversial, and natural selection does
sometimes occur at whole system (hologenome) level, but it is not clear
that this is always the case.
The Baldwin effect, named after the psychologist James Mark Baldwin
by George Gaylord Simpson in 1953, proposes that the ability to learn
new behaviours can improve an animal's reproductive success, and hence
the course of natural selection on its genetic makeup. Simpson stated
that the mechanism was "not inconsistent with the modern synthesis" of
evolutionary theory,
though he doubted that it occurred very often or could be proven to
occur. He noted that the Baldwin effect provided a reconciliation
between the neo-Darwinian and neo-Lamarckian approaches, something that
the modern synthesis
had seemed to render unnecessary. In particular, the effect allows
animals to adapt to a new stress in the environment through behavioural
changes, followed by genetic change. This somewhat resembles Lamarckism
but without requiring animals to inherit characteristics acquired by
their parents. The Baldwin effect is broadly accepted by Darwinists.
In sociocultural evolution
Within the field of cultural evolution, Lamarckism has been applied as a mechanism for dual inheritance theory.
Gould viewed culture as a Lamarckian process whereby older generations
transmitted adaptive information to offspring via the concept of learning. In the history of technology,
components of Lamarckism have been used to link cultural development to
human evolution by considering technology as extensions of human
anatomy.
Epigenetic modifications play a role in the development and
heritability of these disorders and related symptoms. For example,
regulation of the hypothalamus-pituitary-adrenal axis by glucocorticoids plays a major role in stress response and is known to be epigenetically regulated.
As of 2015 most work has been done in animal models in laboratories, and little work has been done in humans; the work is not yet applicable to clinical psychiatry. Stress-induced epigenetic changes, particularly to genes that effect the hypothalamic–pituitary–adrenal
(HPA) axis, persist into future generations, negatively impacting the
capacity of offspring to adapt to stress. Early life experiences, even
when generations removed, can cause permanent epigenetic modifications
of DNA resulting in changes in gene expression, endocrine function and metabolism. These heritable epigenetic modifications include DNA methylation of the promoter regions of genes that affect sensitivity to stress.
Mechanism
Epigenetic
modification in response to stress results in molecular and genetic
alterations that in turn results in mis-regulated or silenced genes.
Heterochromatin is the protein that controls the silencing of these
genes epigenetically. For example, epigenetic modifications to the gene BDNF
(brain derived neurotrophic factor), as well as Drosophila ATF-2
(dATF-2), as a result of stress can be passed on to offspring. Chronic
variable stress induces offspring hypothalamic gene expression
modifications, including elevated methylation levels of the BDNF promoter in the hippocampus.
This methylation will also occur in the heterochromatin, causing a
disrupted heterochromatin to be passed on to the child. Maternal
separation and postnatal maternal abuse also increases DNA methylation
at regulatory regions of BDNF genes in the prefrontal cortex and hippocampus, leading to potential stress vulnerability in future generations.
Stress can also result in inheritable changes DNA methylation in the promoter regions of the estrogen receptor alpha (ERα), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR). These changes lead to altered expression of these genes in offspring that in turn leads to decreased stress tolerance.
Stress and the HPA axis
Gene
regulation as it relates to the HPA axis has been implicated in
transgenerational stress effects. Environmental prenatal stress
exposure, for example, alters glucocorticoid receptor gene expression, gene function, and future stress response in F1 and F2 generations.
Maternal care likewise contributes to HPA-related epigenetic
modifications. Epigenetic re-programming of gene expression alters
stress response in offspring later in life when exposed to decreased
maternal care. Inattentive mothering has led to increased levels of gene
methyl marks, compared to attentive mothers.
Female offspring with low licking-grooming mothers have decreased
promoter methylation and increased histone acetylation, leading to
increased glucocorticoid receptor expression. Epigenetic modifications as a result of absent maternal care lead to decreased estrogen receptor alpha expression, due to increased methylation at the gene's promoter.
Epigenetic writers, erasers, and readers
Epigenetic
changes are performed by enzymes known as writers, which can add
epigenetic modifications, erasers, which erase epigenetic modifications,
and readers, which can recognize epigenetic modifications and cause a
downstream effect. Stress-induced modifications of these writers,
erasers, and readers result in important epigenetic modifications such
as DNA methylation and acetylation.
DNA methylation
During DNA methylation, cytosine is methylated.
DNA methylation is a type of epigenetic modification in which methyl groups are added to cytosines of DNA. It is located on the fifth position of cytosine which has importance in the development of mammals. DNA methylation is an important regulator of gene expression
and is usually associated with gene repression. DNA Methylation is a
mechanism which can suppress gene expression. It can be inherited
through cell divisions in development, and is involved with cell memory.
Changes in methylation occur due to mutated or deregulated chromatin
regulators. This process is also used in marking cancers for diagnosis.
MeCP2
Laboratory studies have found that early life stress in rodents can cause phosphorylation of methyl CpG binding protein 2 (MeCP2),
a protein that preferentially binds CpGs and is most often associated
with suppression of gene expression. Stress-dependent phosphorylation of
MeCP2 causes MeCP2 to dissociate from the promoter region of a gene
called arginine vasopressin (avp), causing avp
to become demethylated and upregulated. This may be significant because
arginine vasopressin is known to regulate mood and cognitive behavior.
Additionally, arginine vasopressin upregulates corticotropin-releasing hormone (CRH), which is a hormone important for stress response. Thus, stress-induced upregulation of avp
due to demethylation might alter mood, behavior, and stress responses.
Demethylation of this locus can be explained by reduced binding of DNA
methyl transferases (DNMT), an enzyme that adds methyl groups to DNA, to
this locus.
MeCP2 is known to have interactions with several other enzymes
that modify chromatin (for example, HDAC-containing complexes and
co-repressors) and in turn regulate activity of genes that modulate
stress response either by increasing or decreasing stress tolerance. For
example, epigenetic upregulation of genes that increase stress response
may cause decreased stress tolerance in an organism. These interactions
are dependent on the phosphorylation status of MeCP2, which as
previously mentioned, can be altered by stress.
DNMT1
DNA
methyltransferase 1 (DNMT1) belongs to a family of proteins known as
DNA methyltransferases, which are enzymes that add methyl groups to DNA.
DNMT1 is specifically involved in maintaining DNA methylation; hence it
is also known as the maintenance methylase DNMT1. DNMT1 aids in
regulation of gene expression by methylating promoter regions of genes, causing transcriptional repression of these genes.
DNMT1 is transcriptionally repressed under stress-mimicking exposure both in vitro and in vivo
using a mouse model. Accordingly, transcriptional repression of DNMT1
in response to long-term stress-mimicking exposure causes decreased DNA
methylation, which is a marker of gene activation. In particular, there
is decreased methylation of a gene called fkbp5,
which plays a role in stress response as a glucocorticoid-responsive
gene. Thus, chronic stress may cause demethylation and hyperactivation
of a stress-related gene, causing increased stress response.
Additionally, DNMT1 gene locus has increased methylation in individuals who were exposed to trauma and developed post-traumatic stress disorder (PTSD). Increased methylation of DNMT1
did not occur in trauma-exposed individuals who did not develop PTSD.
This may indicate an epigenetic phenotype that can differentiate
PTSD-susceptible and PTSD-resilient individuals after exposure to
trauma.
Transcription factors
Transcription factors are proteins that bind DNA and modulate the transcription of genes into RNA such as mRNA, tRNA, rRNA,
and more; thus they are essential components of gene activation. Stress
and trauma can affect expression of transcription factors, which in
turn alter DNA methylation patterns.
For example, transcription factor nerve growth-induced protein A
(NGFI-A, also called NAB1) is up-regulated in response to high maternal
care in rodents, and down-regulated in response to low maternal care (a
form of early life stress). Decreased NGFI-A due to low maternal care
increases methylation of a glucocorticoid receptor promoter in rats. Glucocorticoid
is known to play a role in downregulating stress response; therefore,
downregulation of glucocorticoid receptor by methylation causes
increased sensitivity to stress.
Histone acetylation
During histone acetylation, lysines are acetylated.
Histone acetylation and deacetylation
is a type of epigenetic modification in which acetyl groups are added
to lysine on histone tails. Histone acetylation, performed by enzymes
known as histone acetyltransferases
(HATs), removes the positive charge from lysine and results in gene
activation by weakening the histone's interaction with
negatively-charged DNA. In contrast, histone deacetylation performed by histone deacetylases (HDACs) results in gene deactivation.
HDAC
Transcriptional activity and expression of HDACs is altered in response to early life stress.
For animals exposed to early life stress, HDAC expression tends to be
lower when they are young and higher when they are older. This suggests
an age-dependent effect of early life stress on HDAC expression. These
HDACs may result in deacetylation and thus activation of genes that
upregulate stress response and decrease stress tolerance.
Transgenerational epigenetic influences
Genome-wide association studies have shown that psychiatric disorders are partly heritable; however, heritability cannot be fully explained by classical Mendelian genetics, but rather epigenetics. There are many components in understanding the heritability of psychiatric disorders.
Understanding epigenetic modifications and its ability to impact
epigenomes over generations is vital in analyzing potential behavioral
disorders.
But we must acknowledge the concept of transgenerational epigenetics
(epigenetic inheritance) which is the occurrence in which parents are
able to transfer traits not present in their DNA sequencing to their
offspring; it is the passing of environmentally manipulated traits for
two or more generations without direct DNA alteration.
For example, one study found transmission of DNA methylation patterns
from fathers to offspring during spermatogenesis. Similarly, several
studies have shown that traits of psychiatric illnesses (such as traits
of PTSD and other anxiety disorders) can be transmitted epigenetically
Parental exposure to various stimuli, both positive and negative, can
cause transgenerational epigenetic and behavioral effects.
Parental exposure to trauma and stress
Trauma and stress experienced by a parent can cause epigenetic changes to its offspring. This has been observed both in population and experimental studies.
Biological vulnerability and HPA axis alterations may be observed
after maternal epigenetic programing during pregnancy, leading to
similar modifications in future generations.
Child abuse exposure, for example, is associated with lower baseline
infant cortisol levels as well as modified HPA axis function. Human
studies investigating posttraumatic stress disorder (PTSD) and its effects on offspring have illustrated similar molecular and HPA axis modification and function.
PTSD patients who experienced trauma from genocides or terrorist
attacks frequently exhibited aggressive or neglectful behavior toward
offspring during critical developmental periods, possibly contributing
to permanent glucocorticoid deregulation in offspring. PTSD mothers and children illustrate lower basal cortisol levels and glucocorticoid receptors and increased mineralocorticoid receptors when exposed to stress.
Therefore, developmental experiences, such as stress exposure, may have
critical effects on neuromodulatory mechanisms transgenerationally.
Strong relationships between maternal care and subsequent
epigenetic modification in offspring, similar to that found in animal
models, has been observed in humans. Severe emotional trauma in the
mother, for example, often leads to modified methylation patterns of DNA
in subsequent offspring generations. PTSD exposed offspring illustrate epigenetic modifications similar to that seen in PTSD mothers, with an increased NR3C2 methylation in exon 1 and increased CpG methylation in the NR3C2 coding sequence, leading to alterations in mineralocorticoid receptor gene expression. Additionally, investigation of post mortem hippocampal
tissue indicates decreased levels of neuron-specific glucocorticoid
receptor mRNA and decreased DNA methylation in promoter regions among
suicidal individuals with lifelong stress or abuse exposure.
Epigenetic mechanisms as a result of early life stress may be
responsible for neuronal and synaptic alterations in the brain.
Developmental stress exposure has been shown to alter brain structure
and behavioral functions in adulthood. Evidence of decreased complexity
in the CA1
and CA3 region of the hippocampus in terms of dendritic length and
spine density after early-life stress exposure indicates
transgenerational stress inheritance.
Therefore, environmental and experience-dependent synaptic
reorganization and structure modifications may lead to increased stress
vulnerability and brain dysfunction in future generations.
Transgenerational Stress Effects
Human
models illustrating transgenerational stress effects are limited due to
relatively novel exploration of the topic of epigenetics as well as
lengthy follow-up intervals required for multi-generational studies.
Several models, however, have investigated the role of epigenetic
inheritance and transgenerational stress effects. Transgenerational
stress in humans, as in animal models, induces effects influencing
social behavior, reproductive success, cognitive ability, and stress
response.
Similar to animal models, human studies have investigated the role of
epigenetics and transgenerational inheritance molecularly as it relates
to the HPA system. Prenatal influences, such as emotional stress,
nutrition deprivation, toxin exposure, hypoxia,
increased maternal HPA activity, and cortisol levels may activate or
affect HPA axis activity of offspring, despite placental barrier.
Paternal stress inheritance
Paternal
stress is an important factor in the determination of inheritance of
genes as well as maternal stress inheritance. Factors such as
environment and experiences can alter the epigenetic of paternal genes
as well as in sperm. Epigenetic changes to the DNA in sperm ("epigenetic
tags") prior to conception can be passed to offspring. The paternal
phenotype will be inherited into the offspring due to genetic
information being stored in the sperm. In studies, it is shown as rodent
offspring are fostered mono-parentally and have no direct exposure with
their fathers, offspring born of stressed male rodents provide a good
model for transgenerational stress inheritance. Direct injection of
sperm RNAs to wild type oocytes results in reproducible stress-related
modifications.
Small non-coding RNAs may serve as a potential mechanism for
stress-related genetic changes in offspring. Mouse models of traumatic
early life stress exposure result in microRNA modifications and
subsequent differences in gene expression and metabolic function.
This effect was reproducible by sperm RNA injection, leading to similar
gene modifications in future generations. The novelty of this research
suggests direct mechanisms capable of altering epigenetics by
stress-related factors.
Phenotypic effects
Early life experiences and environmental factors may lead to epigenetic modification at specific gene loci, leading to altered neuronal plasticity, function, and subsequent behavior.
As mentioned, there are genetic markers in all living organisms. There
can also be the presence of epigenetically marks and this are basically
areas of modification on DNA that in with gene expression. Certain
exposures within the environment can lead to the expression of genes in
various ways which can contribute to behavioral plasticity patterns that
can potentially also change the ways in which organism functions when
under normal conditions.
Chromatin remodeling in rodent offspring and altered gene expression
within the limbic brain regions that may contribute to depression,
stress, and anxiety-related disorders in future generations.
Variations in maternal care, such as maternal licking and grooming,
indicates reduced HPA axis reactivity in subsequent generations.
Such HPA axis modifications lead to decreased anxiety-like behavior in
adulthood and increased glucocorticoid receptor levels leading to
negative feedback on HPA reactivity and further behavioral
modifications.
Rodent models of maternal separation also reveal increased
depressive-like behavior in offspring, decreased stress coping
abilities, and changes in DNA methylation.
Irene Shashar, a Holocaust survivor of the Warsaw Ghetto, addressing MEPs
Holocaust
An epidemiological study investigating behavioral, physiological, and molecular changes in the children of Holocaust survivors found epigenetic modifications of a glucocorticoid receptor gene, Nr3c1.
This is significant because glucocorticoid is a regulator of the
hypothalamus-pituitary-adrenal axis (HPA) and is known to affect stress
response. These stress-related epigenetic changes were accompanied by
other characteristics that indicated higher stress and anxiety in these
offspring, including increased symptoms of PTSD, greater risk of
anxiety, and higher levels of the stress hormone cortisol. The offspring demonstrate greater risk of developing PTSD in response to their own trauma or traumas.
Offspring with maternal exposure to the Holocaust during the mother's
childhood has demonstrated significantly lower site 6 methylation.
The site 6 methylation impacts the stress response. In addition to PTSD
risks in response to individual trauma in offspring, there has also
been an increase in nightmares of offspring related to persecution and
torment.
Experimental evidence
The
effect of parental exposure to stress has been tested experimentally as
well. For example, male mice who were put under early life stress
through poor maternal care—a scenario analogous to human childhood
trauma—passed on epigenetic changes that resulted in behavioral changes
in offspring. Offspring experienced altered DNA methylation of
stress-response genes such as CB1 and CRF2 in the cortex,
as well as epigenetic alterations in transcriptional regulation gene
MeCP2. Offspring were also more sensitive to stress, which is in
accordance with the altered epigenetic profile. These changes persisted
for up to three generations.
In another example, male mice were socially isolated as a form of
stress. Offspring of these mice had increased anxiety in response to
stressful conditions, increased stress hormone levels, dysregulation of
the HPA axis which plays a key role in stress response, and several
other characteristics that indicated increased sensitivity to stress.
Inheritance of small-noncoding RNA
Studies
have found that early life stress induced through poor maternal care
alters sperm epigenome in male mice. In particular, expression patterns
of small-noncoding RNAs (sncRNAs) are altered in the sperm, as well as in stress-related regions of the brain.
Offspring of these mice exhibited the same sncRNA expression changes in
the brain, but not in the sperm. These changes were coupled with
behavioral changes in the offspring that were comparable to behavior of
the stressed fathers, especially in terms of stress response.
Additionally, when the sncRNAs in the fathers' sperm were isolated and
injected into fertilized eggs, the resulting offspring inherited the
stress behavior of the father. This suggests that stress-induced
modifications of sncRNAs in sperm can cause inheritance of stress
phenotype independent of the father's DNA.
Parental exposure to positive stimulation
Exercise
Just
as parental stress can alter epigenetics of offspring, parental
exposure to positive environmental factors cause epigenetic
modifications as well. For example, male mice that participated in
voluntary physical exercise
resulted in offspring that had reduced fear memory and anxiety-like
behavior in response to stress. This behavioral change likely occurred
due to expressions of small non-coding RNAs that were altered in sperm
cells of the fathers. Participation in aerobic exercise led to decreased cortisol levels in males.
Stress effect reversal
Additionally,
exposing fathers to enriching environments can reverse the effect of
early life stress on their offspring. When early life stress is followed
by environmental enrichment, anxiety-like behavior in offspring is
prevented. Similar studies have been conducted in humans and suggest that DNA methylation plays a role.
Other studies have been conducted to find drugs such as T2D and PPArG
can be used as an epigenetic regulation for tissues associated with
diabetes. These drugs used show evidence for the therapies that can be
associated with the stress effect reversal.
Childhood exposure to trauma
Early life development and childhood trauma
Mental health disorders that can be caused by epigenetic alterations
Healthy development early in life is critical. Early life is
characterized by rapid development and increased susceptibility to
modifications. Childhood trauma can severely affect the development of
the brain, resulting in the alteration of neural circuits which are
involved in emotional regulation and threat detection. Childhood trauma
has been associated with a wide array of mental health disorders such
as bipolar disorder, anxiety, post traumatic stress disorder (PTSD), and
depression.
PTSD Inheritability
Research involving PTSD
in those who experienced childhood trauma had a 25% to 60%
inheritability rate, which is a relatively low to moderate rate. This
study suggests that other factors play a role in the contribution to
this disorder such as gene interactions involving epigenetic
modifications. These epigenetic modifications, specifically DNA
methylation can lead to the phenotypic expression of mental disorders.
Changes to the HPA Axis Due to Childhood Trauma
Hypothalamic-pituatary-adrenal (HPA)
axis is essential component of the neuroendocrine system that regulates
stress response. Persistent dysregulation of the stress response
pathway resulting from childhood trauma causes alterations in the (HPA).
These alterations lead to prolonged harmful physiological and physical
changes.
Postmortem Brain Tissue DNA Methylation
A DNA methylation
study was done by Labonte on postmortem human brain tissue comparing
humans with or without a history of childhood abuse who died by suicide.
Childhood abuse and trauma was associated with increased cytosine
methylation of the NR3C1 promoter resulting in the decrease of GR
expression. The NR3C1 gene encodes glucocorticoid receptor (GR) which is
essential for glucose regulation and managing stress response through
both genetic and epigenetic pathways.
Post-traumatic stress disorder (PTSD)
Post-traumatic stress disorder
(PTSD) is an stress-related mental health disorder that emerges in
response to traumatic or highly stressful experiences. It is believed
that PTSD develops as a result of an interaction between these traumatic
experiences and genetic factors. The signs and symptoms of PTSD can
include avoidance behaviors, invasive thoughts, and significant
alterations in normal behavior and thinking.
There is evidence suggesting PTSD formation is associated with
epigenetic changes such as DNA methylation and acetylation of histone
proteins. Increased DNA methylation has been found to regulate the
induction of fear conditioning behaviors associated with PTSD triggers.
Histone modifications, like acetylation and deacetylation, play an
important role in the development of PTSD, which is related to fear
memory from traumatic events.
The DSM-5 asserts that PTSD manifests differently in children
over six years old than in adults. Specifically that their flashbacks or
intrusive memories may be explained by recreating their traumatic
event(s) through their play. They may also experience reoccurring
nightmares that are indirectly related to the event. Additionally, there
is a separate criteria altogether for PTSD in children under six years
old.
Epigenetic modifications
DNA methylation
Epigenetic DNA Methylation
Through a number of human studies, PTSD is known to affect DNA
methylation of CpG islands in several genes involved in numerous
activities, including stress responses and neurotransmitter activity.
CpGs are used to describe cytosine-guanine adjacent nucleotides within
the same strand of DNA. CpG islands are defined by computer algorithms
as being made up of at least 60% CpGs and being anywhere between 200 and
3000 base pairs in size. The methylation of these CpG islands can cause
histone modifications which can lead to the condensation of chromatin
which can ultimately alter gene expression.
DNMT enzyme
DNA
methyltransferase, DNMT, is an enzyme responsible for increased
methylation of DNA. It has been found that DNMT and its associated
increased methylation can regulate risk for memory consolidation and fear conditioning.
TET enzyme
The
removal of methyl groups from cytosine is initiated by a TET enzyme.
TET is an enzyme known to oxidize 5-methylcytosine (5mC) to
5-hydroxymethylcytosine (5hmC) within the genome. This reaction
initiates active DNA demethylation to ultimately alter gene expression.
It has been found that the TET enzyme exists as two isoforms which are
differentially regulated and expressed across brain regions. The
regulation of these isoforms can affect synaptic connections and
ultimately memory formation. The manipulation of the TET enzymes' expression levels has become a potential source of interest for PTSD medication.
The table below identifies differentially methylated regions
(DMRs) across the genome which undergo PTSD-induced epigenetic changes
which alter gene expression.
Human Studies Supporting the Role of DNA Methylation in PTSD
Higher methylation is associated with PTSD symptoms.
Histone modifications
Histone
acetylation is performed by histone acetyl transferases (HATs) and
histone deacetylation is carried out by histone deacetylases (HDACs). In rodent PTSD models, it has been found that an increase in histone acetylation is associated with fear conditioning.
Histone acetylation can be involved in all parts of fear memory,
including the development to memory extinction. It can also play a role
in long-term potentiation (LTP).
It was also observed that HDACs increase memory formation in fear
extinction and HDAC inhibitors (HDACi) have shown evidence for modifying
memory extinction, a possible treatment for PTSD.
Nervous system structures affected by PTSD
Hypothalamus-pituitary-adrenal axis
The
hypothalamus-pituitary-adrenal (HPA) axis is a neuroendocrine system
largely involved in ascertaining the levels of cortisol circulating the
body at any given point in time. As cortisol plays a key role in the
stress response, so does the HPA axis. The dysregulation of the HPA axis
has been found to be characteristic of several stress disorders,
including PTSD. This system works under a negative feedback loop
structure. Hence, this HPA axis dysregulation may take the form of
amplified negative inhibition and result in down-regulated cortisol
levels.
Epigenetic modifications play a role in this dysregulation, and these
modifications are likely caused by the traumatic/stressful experience
that triggered PTSD.
Immune dysregulation by HPA axis modifications
PTSD
is often linked with immune dysregulation. Traumatic experiences can
induce epigenetic changes at the gene loci that are immune-related which
can lead to immune dysregulation and an increased risk of PTSD.
Trauma exposure can also disrupt the HPA axis, thus altering peripheral
immune function. The effect of PTSD on immune function arises in at
least two ways: 1) Continuous disturbances on the HPA axis can
dysregulate peripheral immune function, and 2) the effects of immune
dysregulation in the periphery can lead to increased development of PTSD
because of alterations in brain function.
PTSD-associated changes in immune cells found in blood or saliva
can serve as biomarkers that trigger epigenetic changes which are
involved in the pathogenesis of PTSD.
These unique biomarkers serve as means of identifying PTSD subtypes.
Beyond identifying subtypes, these distinct biomarkers can potentially
be used to develop PTSD treatments.
Epigenetic modifications have been observed in immune-related
genes of individuals with PTSD. For example, deployed military members
who developed PTSD have higher methylation in the immune-related gene interleukin-18 (IL-18).
This has interested scientists because high levels of IL-18 increase
cardiovascular disease risk, and individuals with PTSD have elevated
cardiovascular disease risk. Thus, stress-induced immune dysregulation
via methylation of IL-18 may play a role in cardiovascular disease in
individuals with PTSD.
Additionally, an epigenome-wide study found that individuals with
PTSD have altered levels of methylation in the following immune-related
genes: TPR, CLEC9A, APC5, ANXA2, TLR8, IL-4, and IL-2. This again shows that immune function in PTSD is disrupted, especially by epigenetic changes that are likely stress-induced.
Genes affected by PTSD
NR3C1
Nr3c1
is a transcription factor that encodes a glucocorticoid receptor (GR)
and contains many GR response elements. Npas4 is another regulatory
transcription factor also responsible for the regulation of GRs.
Stress-induced changes in Nr3c1 and Npas4 methylation have been shown to
alter stress sensitivity. This response differs between short-lived
stress exposure and chronic stress exposure. In response to short lived
stress, the NR3C1 promoter is more hydroxymethylated which is a
modification associated with increased transcription of GR-associated
genes. Thus, short lived stress exposure increases stress sensitivity.
Conversely, in response to chronic stress, the Npas4 promoter has been
presumed to be increased in methylation, a modification which is
associated with inhibitory regulation of GRs. Thus, chronic stress
exposure decreases stress sensitivity. These distinctions are important
in understanding the epigenetic patterns of stress and genetic
interactions with PTSD triggers.
Overall, in the hippocampus of chronically stressed animals, the 3′-UTR
(untranslated region of DNA) of the glucocorticoid receptor Nr3c1
showed increased hydroxymethylation, which led to increased
transcription and thus, the disruption of stress tolerance and increased
risk of disorders such as PTSD. However, early life stress increases
methylation of the 1F promoter in this gene (or the 17
promoter analog in rodents). Because of its role in stress response and
its link to early life stress, this gene has been of particular
interest in the context of PTSD and has been studied in PTSD of both
combat veterans and civilians.
In studies involving combat veterans, those who developed PTSD had lowered methylation of the Nr3c1 1F promoter compared to those who did not develop PTSD. Additionally, veterans who developed PTSD and had higher Nr3c1
promoter methylation responded better to long-term psychotherapy
compared to veterans with PTSD who had lower methylation. These findings
were recapitulated in studies involving civilians with PTSD. In civilians, PTSD is linked to lower methylation levels in the T-cells of exons 1B and 1C of Nr3c1,
as well as higher GR expression. Thus, it seems that PTSD causes
lowered methylation levels of GR loci and increased GR expression.
The methylation of GR in T-cells are investigated because of its role
in regulating cell immunity which, as such, stores cellular memory with
environmental factors. T-cell fragments from individual cell populations
are preferred over homogenized tissue because of the drastic variation
in DNA methylation patterns between different cell fragments.
Although these results of decreased methylation and
hyperactivation of GR conflict with the effect of early life stress at
the same loci, these results match previous findings that distinguish
HPA activity in early life stress versus PTSD. For example, cortisol
levels of HPA in response to early life stress is hyperactive, whereas
it is hypoactive in PTSD. Thus, the timing of trauma and stress—whether
early or later in life—can cause differing effects on HPA and GR.
FKBP5
Fkbp5
encodes a GR-responsive protein known as Fk506 binding protein 51
(FKBP5). FKBP5 is induced by GR activation and functions in negative
feedback by binding GR and reducing GR signaling. There is particular interest in this gene because some FKBP5
alleles have been correlated with increased risk of PTSD and
development of PTSD symptoms—especially in PTSD caused by early life
adversity. Therefore, FKBP5 likely plays an important role in PTSD.
As mentioned previously, certain FKBP5 alleles are
correlated to increase PTSD risk, especially due to early life trauma.
It is now known that epigenetic regulation of these alleles is also an
important factor. For example, CpG sites in intron 7 of FKBP5 are
demethylated after exposure to childhood trauma, but not adult trauma.
Additionally, methylation of FKBP5 is alters in response to PTSD
treatment; thus methylation levels of FKBP5 might correspond to PTSD
disease progression and recovery.
ADCYAP1 and ADCYAP1R1
Pituitary
adenylate cyclase-activating polypeptide (ADCYAP1) and its receptor
(ADCYAP1R1) are stress responsive genes that play a role in modulating
stress, among many other functions. Additionally, high levels of ADCYAP1
in peripheral blood is correlated to PTSD diagnosis in females who have
experienced trauma, thus making ADCYAP1 a gene of interest in the
context of PTSD.
Epigenetic regulation of these loci in relation to PTSD still
require further investigation, but one study has found that high
methylation levels of CpG islands in ADCYAP1R1 can predict PTSD symptoms
in both males and females.
Alcohol use disorder
Alcohol
use disorder is a type of brain disorder that requires one to have
dependency on alcohol. Alcohol use disorder can vary in severity.
Alcohol dependence can impact stress and other disorders in many ways. For example, stress-related disorders such as anxiety and PTSD are known to increase risk of alcohol use disorder (AUD), and they are often co-morbid.
Mental disorders that pair with AUD can impacts the brain in many ways.
For example, AUD can have the ability to aid those diagnosed with
depression by alleviating depression symptoms such as insomnia,
restlessness, and/ or the ability to re-engage in normal activities, and
re-engage in hobbies. Bipolar disorder can cause manic episodes ranging
fro different sudden mood changes. AUD can also be used to stall the
same symptoms expressed in depression as well as with bipolar disorder.
In some cases AUD can cause other brain disorders to worsen itself, or
the symptoms of the disorder. An example of this can be seen in some
with Obessive-Compulsive Disorder (can typically include anxiety
“triggers” that often cause an individual to have very specific
compulsions or obsessions). With this type of disorder, although it can
help in ways by relieving symptomatic stress, it can also aid in
promoting addiction to alcohol which can be a negative impact if
uncontrolled.
This may in part be due to the fact that alcohol can alleviate some
symptoms of these disorders, thus promoting dependence on alcohol.
Conversely, early exposure to alcohol can increase vulnerability to
stress and stress-related disorders. AUD is a type of epigenetic
influencing disorder, it is able to be passed down generation to
generation epigenetically following a process mentioned before as
transgenerational epigenetics.
Moreover, alcohol dependence and stress are known to follow similar
neuronal pathways, and these pathways are often unable to be regulated
by similar epigenetic modifications.
Histone acetylation
HDAC
Histone
acetylation is dysregulated by alcohol exposure and dependence, often
through dysregulated expression and activity of HDACs, which modulate
histone acetylation by removing acetyl groups from lysines of histone
tails. For example, HDAC expression is upregulated in chronic alcohol
use models. Monocyte-derived dendritic cells of alcohol users have increased HDAC gene expression compared to non-users. These results are also supported by in vivo
rat studies, which show that HDAC expression is higher in
alcohol-dependent mice that in non-dependent mice. Furthermore, knockout
of HDAC2 in mice helps lower alcohol dependence behaviors. The same pattern of HDAC expression is seen in alcohol withdrawal, but acute alcohol exposure has the opposite effect; in vivo, HDAC expression and histone acetylation markers are decreased in the amygdala.
Dysregulation of HDACs is significant because it can cause
upregulation or downregulation of genes that have important downstream
effects both in alcohol dependence and anxiety-like behaviors, and the
interaction between the two. A key example is BDNF (see "BDNF" below).
BDNF
Brain-derived neurotrophic factor
(BDNF) is a key protein that is dysregulated by HDAC dysregulation.
BDNF is a protein that regulates the structure and function of neuronal
synapses. It plays an important role in neuronal activation, synaptic
plasticity, and dendritic morphology—all of which are factors that may
affect cognitive function. Dysregulation of BDNF is seen both in
stress-related disorders and alcoholism; thus BDNF is likely an
important molecule in the interaction between stress and alcoholism.
For example, BDNF is dysregulated by acute ethanol exposure.
Acute ethanol exposure causes phosphorylation of CREB, which can cause
increased histone acetylation at BDNF loci. Histone acetylation
upregulates BDNF, in turn upregulating a downstream BDNF target called
activity-regulated cytoskeleton associated protein (Arc), which is a
protein responsible for dendritic spine structure and formation. This is
significant because activation of Arc can be associated with anxiolytic
(anxiety-reducing) effects. Therefore, ethanol consumption can cause
epigenetic changes that alleviate stress and anxiety, thereby creating a
pattern of stress-induced alcohol dependence.
Alcohol dependence is exacerbated by ethanol withdrawal. This is
because ethanol withdrawal has the opposite effect of ethanol exposure;
it causes lowered CREB phosphorylation, lowered acetylation,
downregulation of BDNF, and increase in anxiety. Consequently, ethanol
withdrawal reinforces desire for anxiolytic effects of ethanol exposure.
Moreover, it is proposed that chronic ethanol exposure results in
upregulation of HDAC activity, causing anxiety-like effects that can no
longer be alleviated by acute ethanol exposure.
The most common treatments for anxiety disorders at the moment are benzodiazepines, Buspirone, and antidepressants.
However, around one/third of patients with anxiety disorders do not
respond well to the current anxiolytics, and many others have
treatment-resistant anxiety disorders. Recent research surrounding DNA methylation changes in genes in genes
encoding proteins associated with the HPA axis, histone modifications,
and sncRNAs point to epigenetic drugs potentially being effective
treatment methods for anxiety disorders.
HDACi are currently being researched as potential anxiolytics. At
the moment, the mechanism of action of HDAC inhibitors in the treatment
of anxiety disorders is not clear, as they affect several targets and
have multiple pharmacological effects besides the inhibition of HDACs.
However, they have been shown to cause DNA demethylation, possibly due
to an increase in the levels of TET1, which is a demethylating enzyme. In the human peripheral cells of patients with anxiety disorders and in animal models of anxiety disorders, genes such as GAD1, NR3C1, BDNF, MAOA,
HECA, and FKBP5 are shown to be hypermethylated. As such, the mechanism
of action of HDACi in anxiety disorders could, in part, be potentially
explained by the demethylation of those genes.
Valproate
Valproate
is a drug that acts as an HDACi on class I and II HDACs. Six clinical
trials surrounding its use as an anxiolytic have been performed so far.
Five of the six trials were performed on patients with anxiety
disorders, and one of the trials used healthy subjects with no anxiety
disorders. Of the five trials performed on patients with anxiety
disorders, three found that Valproate decreases panic disorder, one
found that Valproate decreases social anxiety, and one found that
Valproate reduces generalized anxiety.
The trial performed on healthy subjects found that Valproate reduces
anxiety and also acts as a nerve conduction inhibitor, which could be an
explanation for some of its anxiety-reducing effects.
D-cycloserine, Trichostatin-a, Suberoylanilide hydroxamic acid, sodium butyrate, and valproic acid
Various
preclinical drug trials using other HDAC inhibitors have also been
performed, with most drugs targeting HDAC classes I and II and a select
few targeting classes IV and III. The HDACi drug, d-cycloserine,
was found to reduce fear in 129S1/SvImJ mice, which are mice that show
poor extinction acquisition and recovery of fear-induced suppression of
heart-rate variability, enlarged dendritic arbors in basolateral amygdala neurons, and functional abnormalities in cortico-amygdala circuitry that mediates fear extinction. Trichostatin-a was normalized BDNF and Arc expression in the central and the medial nucleus of the amygdala in rats experiencing alcohol withdrawal. Suberoylanilide hydroxamic acid significantly reversed anxiety-like behaviors and stress-induced gastrointestinal hypersensitivity and fecal pellet output. Anxiety-like and depression-like behaviors caused by immobilization stress or nicotine addiction were also reduced in mice treated with the HDACi sodium butyrate and valproic acid.
Lactate
Lactate, a metabolite
that is naturally produced during exercise, was found to function as an
HDAC II and III modulator in a pre-clinical trial. The trial was
performed on C57BL/6 mice, which are mice that were exposed to chronic
stress in the form of daily defeat by a CD-1 aggressive mouse. While
control mice exhibited increased social avoidance, anxiety, and
susceptibility to depression, mice that received lactate before each
defeat demonstrated resilience to depression and stress and reduced
social avoidance and anxiety. Lactate promoted this resilience by
restoring regular hippocampal class I HDAC levels and activity.
sncRNA
Preliminary
research has been done about therapy involving small non-coding RNAs,
demonstrating that they can regulate epigenetic mechanisms of gene
expression and could present as biomarkers for disease. One therapy option is for the sncRNAs in patients with anxiety disorders to be targeted for upregulation. Another option is to inhibit the miRNAs in order to reduce their effects, potentially using antisense oligonucleotides or antagomirs as inhibitors.
Hydrocortisone
The medication hydrocortisone is a synthetic form of cortisol, and is typically an anti inflammatory.
In recent years, the administration of hydrocortisone has been tested
as a possible preventative measure for the onset of PTSD symptoms.
Ideally, it should be administered immediately after a traumatic event.
The efficacy of hydrocortisone as a preventative intervention for PTSD
has been confirmed by a meta-analysis of eight separate studies, and
researchers believe the best results are obtained when hydrocortisone is
administered within the first six hours of exposure to the traumatic
event. At this time, however, no curative properties have been
discovered.
Hydrocortisone's potential operates on two bases: restoration of normal
HPA axis functioning and interference with memory consolidation.
HPa axis homeostasis
Our
standard understandings of PTSD may suggest elevated glucocorticoid
levels during and directly following events of trauma. However, multiple
studies have indicated that overall HPA axis activity and cortisol
levels are depleted in the critical aftermath and extended period after
trauma.
Moreover, research has also indicated that an appropriate release of
glucocorticoids following acute stress may restore homeostatic
equilibrium of the HPA axis, thereby preventing gradual sensitization,
which is responsible for persistent cortisol reduction and increased
PTSD susceptibility. Thus, the appropriately-dosed administration of
hydrocortisone promptly following the traumatic incident would normalize
the HPA axis and potentially prevent PTSD onset.
Disruption of memory consolidation
In
the absence of memory reactivation, hydrocortisone's effectiveness
within a six-hour window supports the consolidation theory, which
asserts that memory is labile even immediately after trauma. It is
assumed that the medication is disrupting initial memory consolidation
of the traumatic event. However, its exact mechanism within this context
remains largely unknown.
Although trials have proven promising, there is much more
research to be done. Further comprehensive studies are required amidst
more diverse populations under different traumatic conditions in order
to ascertain factors of optimal usage of the drug and clarify the PTSD
subgroups hydrocortisone is beneficial to.
Rodent models used to study PTSD medication
Stress-enhanced fear learning (SEFL)
The
observation of epigenetic modifications and their role in regulating
fear learning is an active area of research. The use of stress-enhanced
fear learning (SEFL) paradigms are important for forming preclinical
models of PTSD because one is able to observe the epigenetic changes in
rodents and PTSD associated changes in fear learning after stress
exposure.
Single-prolonged stress (SPS)
The
single-prolonged stress (SPS) model is a tool in which a complex
stressor is consistently presented. This tool is used to explore the
complexity of PTSD, particularly its impaired fear extinction.
Susceptible factors to PTSD
Despite
high levels of individuals exposed to trauma, only about one third of
exposed individuals develop PTSD. This suggest that individuals differ
in their susceptibility to PTSD. This might arise from differences in
the epigenetic modifications that they generate in response to traumatic
experiences. Furthermore, a large area of research regarding increased
susceptibility to PTSD investigates the transgenerational inheritance of
epigenetic modifications resulting from trauma.
A recent review of PTSD susceptibility suggested that a range as wide
as 30% to 70% of susceptibility to PTSD can be attributed to
heritability.
From our observations of mice in transgenerational research, we have
seen that the epigenetic modifications that stem from trauma can be
passed down multiple generations.
Epigenetic modifications due trauma are not the only heritable factors
that affect PTSD susceptibility. General histories of health
deficiencies, both physical and psychological, have also been associated
with a higher PTSD susceptibility. Sociodemographic factors may come
into play as well. Particularly, ethnic minorities and women are more
susceptible to development of PTSD.
