Accepted Manuscript

Can memory exist outside of brain and be transferred? Historical review, issues
& ways forward

Ghulam Abbas, Wajahat Mahmood, Faisal Khan

PII: S0306-9877(17)30455-3
DOI: https://doi.org/10.1016/j.mehy.2017.10.003
Reference: YMEHY 8698

To appear in: Medical Hypotheses

Received Date: 29 April 2017

Accepted Date: 5 October 2017

Please cite this article as: G. Abbas, W. Mahmood, F. Khan, Can memory exist outside of brain and be transferred?
Historical review, issues & ways forward, Medical Hypotheses (2017), doi: https://doi.org/10.1016/j.mehy.
2017.10.003

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 CAN MEMORY EXIST OUTSIDE OF BRAIN AND BE TRANSFERRED?

HISTORICAL REVIEW, ISSUES & WAYS FORWARD

Running title: Body memory: Old connections, new hopes

Authors: Ghulam Abbas1*, Wajahat Mahmood2 and Faisal Khan3

Affiliation:

1
H.E.J. Research Institute of Chemistry, International Center for Chemical & Biological

Sciences, University of Karachi, Karachi-75270, Pakistan

2
Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad-22060,

K.P.K., Pakistan

3
Dr. Panjwani Center for Molecular Medicine & Drug Research, International Center for
Chemical & Biological Sciences, University of Karachi, Karachi-75270, Pakistan

*Corresponding author:

Dr. Ghulam Abbas

H.E.J. Research Institute of Chemistry, International Center for Chemical & Biological Sciences,

University of Karachi, Karachi-75270, Pakistan

Tel: (92-21) 34824924-5: Ext 137

Fax: (92-21) 34819018-9

E-mail: ghulam.abbas@hotmail.com

ghulam.abbas@iccs.edu

1
ABSTRACT

Learning and memory are among the executive functions attributed to intelligent forms of life.
Unfortunately, there is a lack of clear understanding regarding the underlying mechanisms
governing these functions. Most of the modern day scientists attribute these functions solely to
brain. However, in the latter half of last century, a number of reports suggested existence of
extra-cranial memory and potential of its transfer between animals. Some have linked this
phenomenon to RNA while others believed that peptides were responsible. The terms like
“educated RNA” and “scotophobin” were coined. This atypical work involving flatworms, yeast
RNA and scotophobin was received with deep skepticism and ultimately disregarded. However,
the recent reproduction of some of this earlier work by scientists at Tufts University has reignited
the debate on the mechanisms of learning and memory. Keeping this in view, we believe it is
high time to summarize this historical work and discuss the possibilities to delineate these
atypical claims. The objective is to incite the present day researchers to explore this opportunity
under the perspective of newer advancements in science.

Key words: Cellular Memory; Flat worm; Yeast RNA; Ribonucleic acid; Scotophobin

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 1. INTRODUCTION

Learning and memory are among the executive functions that constitute cognition. The former is
the process of acquiring new information, while later is the process of storing it. Memory is
actually a change in response to the experience, which helps in developing more appropriate
response upon next stimuli. “What actually this change is” and “where it happens” are the
questions commonly encountered by scientists working in this area. These questions have mainly
remained unanswered despite the enormous data generated by modern neuroscience. The older
concepts such as synaptic plasticity and long term potentiation are generally used to describe the
formation and storage of memories in the brain (1-2). The flat-lining of progress in this area can
also be reflected from the failure in development of drugs used to treat the memory disorders.
For instance, Alzheimer is the leading cause of dementia and forecasted to affect 1 in 85 humans
by the year 2050 (3). It progresses insidiously with an average life expectancy of about 7 years
for the patients after diagnosis (4). Various underlying mechanisms have been proposed to
explain the pathogenesis of Alzheimer’s disease, including amyloidosis, Tau protein
hyperphosphorylation, oxidative stress, and mitochondrial alterations (5). However, none of the
aforesaid attributes has led to the development of drug(s), which can offer permanent cure.
Hence, the situation presses the need of identifying newer therapeutic targets. In this regard, the
understanding of the phenomenon of learning and memory is inevitable. A search of the
literature revealed that much of the present day research is focused on studying mechanisms
underlying neurodegeneration, and identification of compounds offering neuroprotection. On the
contrary, reports describing the physiology of learning and memory are seldom encountered. A
considerable amount of work done on the basics of memory during the last century resulted in
the noble prize in 2000 for Eric Kandel, Arvid Carlsson, and Paul Greengard, and for O'Keefe,
May-Britt Moser and Edvard Moser in 2014. However, at the same time, the enormous work
carried out on body / cellular memory and transferable potential of memory remained in grey
area and forgotten.

2. CAN MEMORY EXIST OUTSIDE OF BRAIN?

Learning and memory have been the topics of interest since the days of emergence of modern
neuroscience. The brain became the focused organ of study and neurons were considered as the
sole players. Even Ramon Cajal associated memory with neuronal growth. Decades of research

3
and reports led to the deep rooting of these concepts in the scientific community and seldom
questioned (6). Outside these overwhelming beliefs exists the neglected science of memory
outside brain, generally termed as body or cellular memory. According to this, the entire body
and its cells are capable of storing memories. It is in line with the notion that all living beings,
irrespective of presence of brain, have the ability to learn and memorize (7). In case of living
beings, the organisms which lack proper brain (Aneural) demonstrate the signs of primitive
learning and memory, which is generally of cellular origin. For instance, the slime mold was
shown to learn the patterns of electric pulse, predict and modify its behavior accordingly (8).
This simple creation was shown to be intelligent enough to find minimum length solution
between two points (9) and shown to be smart and possess intelligence (10). These reports
showed that cells, not only neurons, are smart and endowed with the potential to perceive the
signal, interpret, and modify response according to the need. Furthermore, the brainless plants
are generally ignored in discussions about cognition. However, the evolutionary changes to adapt
for harsh climatic conditions (temperature, salinity etc) are actually the changes in response to
experience and should be taken as memory. It is worth mentioning that plants are reported to
exhibit the signs of intelligence through their behavior (11). How the plant pay attention to
environmental stimuli is suggested to be the point of focus for plant intelligence studies (12).
Furthermore, the intelligent temperature detection system was reported in Arabidopsis seeds,
which plays decisive role in terminating dormancy (13). The root tips, also called as root brains,
along with motility and sensoriomotor organization was reported to constitute the system
responsible for cognition (14). It is of note that the plants are reported to possess action potential
(15), which can be blocked by anesthetics (16). Hence, they also possess animal like features
generally assumed as requirements for cognition.

Bacterial resistance, efflux pumps in cancerous cells, phantom pains and sperm running are also
the examples of extra neural learning. The cells do not required brain to learn and memorize.
However, taking into account the organisms with centralized brain, the involvement of peripheral
cells in learning and memory is generally considered irrelevant. The pioneering work in this
regard was performed by McConnell in the middle of last century. He performed his experiments
on the flatworms, which possesses centralized brain and remarkable ability to regenerate when
chopped into small pieces. He trained the flatworm in a behavioral task followed by decapitation.
It is of note that the re-grown flatworm showed the signs of training despite of the development

4
of entirely new brain (17). What the tail remembered is not known till date but this evidence
bolstered the idea of cellular memory in complex form of life as well. In conformity, human
bone (18), muscle (19), pancrease (20) and heart (21) are also shown to exhibit traces of
memory. Hence, it is proposed that the biogenic approach, in contrast to anthropogenic, should
be adopted in order to grasp the science of learning and memory more efficiently (22). In this
scenario, the recent work conducted at Tufts University has revived an interest in the findings of
McConnell on the existence of memory outside brain (23).

3. CAN MEMORY BE TRANSFERED VIA RNA?

McConnell further surprised the world with the report suggesting that the cannibalism of light-
shock conditioned planaria enhanced the ability to learn the situation in fewer trials as compared
to naïve planaria (24). This experiment led to the basis of “memory transfer hypothesis”. As
expected, the next attempt was to find out which bio-molecule carried the memory. In this
regard, the transfer of extracted RNA was found to be responsible (25). The addition of RNAase,
not DNAase or trypsin hindered the retention and transfer of memory (26). Hence, he concluded
that RNA is the engram and can be transferred. His work received tremendous attention as well
as skepticism. Researchers started to reproduce his work. Some found similar results such as the
use of ribonucleases was shown to block the retention of conditioned response in the regenerated
flatworm planarian tails (27). RNA based memory transfer was also shown in rats (28), and the
same group reported an extremely exciting finding that the transfer of memory can also happen
between species (29). Another group reported the potential role of RNA in transfer of memory
in rats (30). The RNA extracted from the brain of trained rats was again shown to enhance the
learning in naïve rats in passive avoidance of dark chamber (31). Taken together, the
aforementioned studies supported possibility of both extra-neural learning and role of RNA as
engram. On the other hand, several other researchers failed to reproduce the results obtained
from McConnell’s experiments. This included the set of experiments which supported the role of
cannibalism in memory transfer, but attributed this to nutritional, metabolism, activation and
sensitization factors (32). In other words, the cannibalism gave physical strength and mental
activation to the animals thereby increasing its performance in memory related tasks. These
outcomes has decreased the overall acceptability of McConnell’s deductions and slowly faded
from the scientific discussions. Furthermore, the arousal factor and lack of detailed mechanistic

5
studies has also contributed in diluting the claims (33). More recently, the flatworm experiments
were successfully reproduced by scientists at Tufts University, using more sensitive automated
behavioral training apparatus (23), thereby rejuvenating the forgotten claims of McConnell.

i) Is RNA itself an engram or a mediator?

After McConnell’s experiments, RNA has received considerable attention as a memory

molecule. The fundamental questions emerging were: a) Is RNA itself a memory molecule or
just an intermediate in the formation of memory? b) Are changes in RNA contents a cause or
effect of behavioral change? (34). A search of literature revealed numerous reports exhibiting the
increase in RNA contents in response to learning and memory. For instance, the RNA content of
lateral vestibular nucleus of rat was shown to be increased after motor learning task (35).
Avoidance learning was correlated with increased hippocampal RNA synthesis (36). During this
era, the influence of aforementioned reports on scientific community could be gauged from
timely reviews on the role of RNA in memory (37-38). These concepts were further strengthened
by reports suggesting inhibition of memory formation in the presence of inhibitors of RNA
synthesis such as actinomycin D (39) and 2,6 diaminopurine (40). In similar lines, 8-Azaguanine
(purine analog) hampers the formation of new memory in maze test without affecting the ability
to recall previously learned maze (41). Azaguanine was also shown to delay the fixation of
experience, while 1-1,3-tricyano-2-amino-l-propene, which increases RNA concentration in
brain, expedited it (42). These set of experiments developed great deal of interest in exploring
the possibility of ‘educated RNA’ as engram. The idea was further reinforced by report from
Cameron and Solyom, which showed positive effect of yeast RNA on the memory of aged
patients suffering from dementia (43). Memory is often explained as a three stage phenomenon,
including acquisition, consolidation (retention) and retrieval. Malfunction of any of these could
potentially cause dementia. The question as to which step of memory is affected was answered
by the same group, suggesting ‘retention of memory’ as the prime target of RNA administration
(44). These reports attracted considerable attention in delineating the relationship between yeast
RNA and memory. It triggered series of experiments exploring the role of yeast RNA in the
various memory related paradigms. In rats, the yeast RNA administration not only enhanced the
rate of pole climbing learning in order to avoid shock, but also resisted extinction learning (45).
As mentioned above, the use of ribonucleases was shown to block the retention of conditioned

6
response in the regenerated flatworm planarian tails (27). These reports were in conformity with
the aforementioned work suggesting retention of the memory as a consequence of the introduced
RNA. Ideally, these outcomes should have triggered initiation of work specifically on the
retention (consolidation) part of complex memory phenomenon. Our literature search could not
find a single report describing progress along this important avenue. Hence, this intriguing topic
is still awaiting the attention of the researchers. The case for the role of yeast RNA in memory
was weakened by certain reports exhibiting lack of effectiveness in learning tasks such as Y-
maze (46), learning of food motivated brightness discrimination (47), and approach to food cup
in response to click (48). Corson and Enesco performed several sets of experiments and showed
that yeast RNA administration increased learning behavior in certain tasks (pole climbing), while
it failed to do so in others (49). This, although inconclusive, was suggestive of differential effects
of yeast RNA administration depending upon the nature of tasks. The specific memory
enhancing ability in pole climbing tasks raised doubt that RNA administration was probably
increasing the strength of the animals (32, 50). However, these doubts were erased as RNA
administration was not found to affect nervous stimulation, endurance and strength of the
animals (49). These findings support the idea that exogenous RNA administration has a role to
play in memory, especially its retention part. Moreover, another fundamental question which
arises is that which type of RNA is acting as the engram; messenger, transfer or ribosomal?
These different forms of RNA have also complicated the situation since development of RNA-
memory nexus (51). However, some work in this regard was performed in context of differences
in nitrogenous base composition. Studies revealed changes in ratio of adenine bases of brain
ribosomal RNA. The AMP-level exhibited increase, while GMP showed corresponding decrease
in adult as compared to newborn rodents. The ribosomal RNA increased by 3-fold in adulthood
and its concentration was found to be higher in adult brain. It is of note that no significant
difference was observed in ratio of pyrimidine bases (52). In another study, the adenine to uracil
ratio of Deiter’s nerve cells nuclear RNA (35), and associated glial cells (53), was shown to be
significantly increased in rats subjected to balance learning. This study also points towards the
involvement of non-neuronal cells in memory. In another set of experiments, Hyden and
colleagues showed that the initial learning (handedness shift) phase was associated with
formation of small amount of adenine and uracil rich RNA in cortical neurons. However, the
later part of learning correlated with the formation of larger amount of RNA with ribosomal type

7
base composition (54). This differential effect may explain the basis of short and long term
memories. In another study, the learning associated increase in cortical RNA was attributed to
enhancement of mRNA (55), which is suggestive of increase in protein synthesis. Taken
together, these reports suggest the importance of individual nitrogenous bases in learning and
memory. Studies have revealed that similar sort of “nucleotide rearrangement hypothesis of
memory” could not receive much attention in the past, and needs to be re-assessed in context of
newer advancements in neurosciences (56). More recently, the senescence linked memory loss
was also related to the oxidation of nucleic acids, especially RNA (57). Oxidative stress is one of
the hallmarks of aging. Hence, the oxidative stress – RNA – Memory link also warrants further
investigation to decipher the role of RNA in memory, either inside and/or outside the brain.

ii) Can RNA cross blood brain barrier?

As a logical follow-up to flatworm and yeast RNA experiments, researchers started to probe the
ability of administered RNA to cross the BBB in higher animals. It is of note that the intra-
peritoneal administered RNA was reported to degrade quickly with high visibility in liver,
kidney and amino acid pool of the body. Consequently, its penetration in the brain was extremely
low accompanying slight increase in protein synthesis (58). Another study reported that the
radio-labeled yeast RNA could not cross the blood brain barrier (59). On similar lines, the lack of
penetration of exogenous RNA to neural tissue was noted (60). Taken together, it was assumed
that RNA itself is not responsible for memory enhancing effect observed in both animals and
humans. These reports related to the fate of exogenous RNA seemed to have burst the bubble of
yeast RNA-memory axis. Some other researchers also denied the link between RNA and engram
(42). Consequently, this led to lack of further exploration in this avenue and issue remained
elusive till date.

4. CAN MEMORY BE TRANSFERED VIA PEPTIDES?

Georges Unger was also among the leading advocates of memory transfer hypothesis. He
reported that the attribute of morphine tolerance was transferred to naive animals when fed on
the brain homogenate of morphine tolerant animals. (61-62). He has further shown that
intraperitoneal injection of brain homogenate from habituated rats fastened the rate of
habituation for a startle response against loud sound. It is of note that this transfer was

8
diminished upon treatment of homogenate with chymotrypsin. This is again suggestive of
potential role of some protein, which is contrary to McConnell’s deductions about RNA as
engram (63). This work has also observed deep skepticism and numerous failed to reproduce it.
Many attributed this transfer to the effect of stress and arousal and consider it non-specific. In
response, Ungar performed experiments to demonstrate that the transfer is indeed specific. The
brain extract of sound habituated rats was shown to affect the sound habituation alone, not the
air-puff startle response and vice versa (64). He has further shown the specificity of memory
transfer in left-right brightness discrimination (65). In order to describe the molecular basis of
memory, he put forwarded a concept of neural connector unique for a particular stimulus. It is
released upon firing of pre-synaptic neuron and makes connection with nearby firing post-
synaptic neuron. Upon repetitive firing, this connection becomes strengthened and lead to a
specific memory trace for a particular experience (66). This concept is in line with the famous
hebbian’s concept of learning and memory (67). In the same year, he has further shown the
transfer of learned fear and attributed it to small peptide (6-10 amino acids) (68). This peptide
was later completely characterized and named as “Scotophobin” (69). Later, this peptide was
widely used by other researchers but failed to produce fear avoidance. Despite of this outcome,
Ungar continued to advocate for the role of peptides through his research (70) and reviews (71-
72), but the scotophobin was slowly erased from the scientific discussions and its chemical
nature remains elusive to date(73).

5. ISSUES & WAYS FORWARD

The lack of reproducibility of flatworm, yeast RNA and Scotophobin experiments by majority of
scientists has led to their exclusion from scientific discussions. In this scenario, the recent
reproduction of McConnell’s result by scientists at Tufts University has again revitalized his
forgotten claims. The technology has revolutionized since last century and numerous questions
related to these experiments can be explicitly answered today. Since, there has only been slight
progress towards explanation of learning and memory in the modern neuroscience; it is worth
exploring this alternate hypothesis and related body of evidence under the context of newer
advancements in science. For instance, the modern day sequencers can precisely assess the
nucleotide re-arrangement theory. Furthermore, the advancement in drug delivery systems,
including the ability to cross blood brain barrier (BBB), is also one of the possible way forward.

9
In this regard, RNA was shown to cross BBB with the help of exosomes (74). Hence, the RNA,
as well as peptides extracted from trained animals can be packaged in these carriers and tested
for their ability to enhance learning in naïve animals. Nevertheless, the role of non-coding RNAs
in both physiology and pathology is also rapidly emerging. Early this century, the interference
RNA was proposed to be the magical molecule underlying the McConnell’s memory transfer
hypothesis (75). Furthermore, micro RNA loss was also shown to correlate with enhanced
learning and memory in mice (76). The role of periphery in memorization is also supported by
reports on experience dependent methylation patterns of DNA in germ cells of traumatized
animals and plants, and their transfer to offspring.(77-78). Such methylation signature is
observed thus far in traumatic memories alone raising the possibility that endangerment of life
probably necessitates the transfer of memory to offspring through any possible means such as
involvement of germ cells, which are located in the periphery.

The rejection of claims from aforementioned experiments was justified at that time because there
was not much known about reverse communication, i.e., from periphery to the brain. In this
regard, starvation, exercise and gut-flora can be taken as examples, and were shown to affect the
performance of animals, including memory. Intermittent starvation was shown to ameliorate the
occurrence of Alzheimer’s disease (79). It is worth noting that this starvation was reported to
increase the synthesis of ketone bodies in the periphery, which holds the ability to affect the
function of the brain, most probably through epigenetic mechanisms (80). Exercise was also
shown to have beneficial effects on memory, which is attributed to brain derived neurotrophic
factor (81). Most recently, the emerging gut-brain axis can also be taken as an example of
periphery to central means of communication (82). Even in the present century, there are some
reports supporting earlier deductions of yeast RNA experiments. For example, the mixture of
Nucleoside-Nucleotide was shown to reduce memory deterioration in old senescence-accelerated
mice (83). Another study reported that the memory-deficient senescence-accelerated mice and
mice with dementia showed improved memory with dietary nucleosides and nucleotides
supplementation (84). It might be that the administration of exogenous RNA enhances the
capacity of animal to learn. In other words, the raw material required to note experiences
increases through this administration. However, the question as to how RNAs contribute to
memory formation, if unearthed, can bring revolution in the field of neuroscience (85).
Collectively, these studies emphasize the need to re-address the once neglected theory of RNA

10
based memory using modern day drug delivery systems, non-coding RNAs and concepts of
peripheral-to-central communication (Figure-1).

Another important question in this regard is that aforementioned results are probably limited to
simpler forms of life like mold and flatworm. In this context, some earlier experiments have also
shown chemical transfer of memory, via RNA, in higher animals like rat and hamsters (28-30).
These experiments need to be performed in primates in order to pave the route towards clinical
utility. It is worth mentioning that memory has numerous types and is composed of processes
like acquisition, consolidation and retrieval of information. Similarly, RNA also has different
types and composition. This built-in complexity is one of the major factors restricting the
outcome of significant scientific work in an explicit manner. Therefore, these aspects should also
be considered while designing the scientific work on learning and memory.

In conclusion, the synaptic plasticity, long term potentiation and associated expression studies
have long served as the axis of rotation for learning and memory related work. The therapeutic
utility of this axis demonstrate stagnation of progress, which press upon the need of exploring
newer avenues. In this regard, the in-conclusive claims from flatworm, scotophobin and yeast
RNA experiments merits further investigation in context of newer advancements in sciences. The
use of biogenic approach, exosomes, concept of peripheral-to-central communication, and role of
non-coding RNAs are the possible ways forward to delineate these old claims. Is it McConnell’s
RNA or Ungar peptide? What they actually are? Do they have some role to play in memory? Can
memory be transferred? These questions should be addressed using modern day technology. If
done so, the history may change the future.

CONFLICTS OF INTEREST

The authors declare no conflict of interest

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 FIGURES TITLE & LEGEND

Figure-1 Effect of RNA administration on performance in maze test

The figure depicts that the administration of RNA extracted from the brain of trained animal
enhances the performance of naïve rats in the similar task. The fate of the administered RNA is
as follows: a) It cannot cross BBB, therefore direct action on brain is not possible b) It can be
transferred to brain encapsulated in the exosomes c) It could possibly exert its primary action in
periphery followed by secondary response in the brain.

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