Memory enhancement: The progress and our fears

Abstract

In a recent article Rose (2002) raises numerous crucial issues with regard to the research into and the use of cognition or memory enhancing agents. Although development of 'smart' drugs is in its infancy, his paper delineates some issues society may have to face when these drugs arrive. Questions about the development of such drugs may be interesting to several readers of Genes Brain and Behavior given the wealth of information expected to be gained on brain function from studies using genetic approaches including mutagenesis, transgenic techniques and genomics in general. Besides the scientific questions, several ethical issues may need to be addressed that are of interest to us all. Rose (2002) discusses some of these questions, but perhaps presents a too negative view on the problems, especially with regard to the present and future of memory research. This paper is intended to focus mainly on the scientific questions and argues that our fear of complex ethical problems should not make us throw the baby (i.e., our research and discoveries) out with the bath water.

Full text

Debate
Memory enhancement: the progress and our fears
R. Gerlai
1
Vice President of Research, Saegis Pharmaceuticals, Inc., 60
Stone Pine Road, Suite 200, Half Moon Bay, CA 94019, USA.
E-mail: robert@saegispharma.com
In a recent article Rose (2002) raises numerous crucial
issues with regard to the research into and the use of
cognition or memory enhancing agents. Although devel-
opment of ‘smart’ drugs is in its infancy, his paper
delineates some issues society may have to face when
these drugs arrive. Questions about the development of
such drugs may be interesting to several readers of
Genes Brain and Behavior
given the wealth of infor-
mation expected to be gained on brain function from
studies using genetic approaches including mutagen-
esis, transgenic techniques and genomics in general.
Besides the scientific questions, several ethical issues
may need to be addressed that are of interest to us all.
Rose (2002) discusses some of these questions, but per-
haps presents a too negative view on the problems,
especially with regard to the present and future of mem-
ory research. This paper is intended to focus mainly on the
scientific questions and argues that our fear of complex
ethical problems should not make us throw the baby (i.e.,
our research and discoveries) out with the bath water.
Keywords: Cognition, learning, memory enhancer, smart
drug
Received 19 February 2003, revised 25 March 2003,
accepted for publication 25 March 2003
The status of cognition research today may not allow a clear
projection as to how exactly ‘smart drugs’ i.e., memory
enhancing agents, will work or when they will be available.
Nevertheless, the skepticism exhibited by some who argue
finding such drugs is impossible is perhaps not warranted.
Rose, for example, explains that our wish for ‘magic potions’
to enhance our ‘wisdom’ is ‘age old’ yet so far drugs tested
‘in humans have proved to be ineffective at enhancing
learning and memory’ (Rose 2002), a statement that is only
partially true. For example, Aricept
Õ
(donepezil), an
acetylcholinesterase inhibitor has shown efficacy both in
Alzheimer’s disease patients (for example Matthews et al.
2000) and in normal human subjects as well (Yesavage et al.
2002). It is also important to realize that the accumulation of
knowledge on the mechanisms of memory shows an expo-
nential increase, and this knowledge will be fundamental in
designing therapies. For example, by now we know that N-
methyl-D-aspartate (NMDA-R) plays a crucial role as a coin-
cidence detector of two converging stimuli, one pre- and one
postsynaptic (see review by Tsien 2000). We have also dis-
covered that CamKII ‘remembers’ its activation as it enters a
self-maintaining autophosphorylation cycle that keeps the
protein activated for several minutes (short-term memory at
the molecular level, see review by Lisman et al. 2002), that
Cyclic-AMP Responsive Element Binding protein (CREB) is
required for the protein synthesis dependent phase of plas-
ticity (longer term memory at the molecular level, for review
see Silva et al. 1998) and that G-protein coupled receptors
(GPCRs) play important modulatory roles, for example
mGluR’s often having facilitatory (for review see Riedel &
Reyman 1996) and GABA
B
inhibitory effects (for review see
Collingridge et al. 1992) to mention but a few important
discoveries of the molecular mechanisms involved in memory.
At the microstructural level we now have evidence that neuro-
nal plasticity is associated with structural modification of the
synapse (Edwards 1995), and at the macrostuctural level we
now know not only that different temporal phases of memory
exist, but also particular brain regions subserve different forms
of memory, for example relational (hippocampus), fear asso-
ciated (amygdala), procedural (cerebellum), etc. (for review see
Zola-Morgan & Squire 1993). Two decades ago much of this
knowledge was non-existent.
Genetic manipulation has had and will continue to have a
crucial impact on acquiring such knowledge. A Medline
(http://research.bmn.com/medline) search for the words
‘memory’ and ‘genetics’ brings up 4592 articles for the
period between 1966 and 2003. For the past decade alone
(1993–2003) however, the search results in as many as 3732
publications. Clearly, genetic analysis of learning and mem-
ory is a prolific field of science. For example, mice genetically
modified with the use of transgenic or gene targeting
methods have been put to use in the analysis of learning
and memory (Lipp & Wolfer 1998). Similarly, chemical
1
Dr Gerlai is employed by Saegis Pharmaceuticals, Inc., which
develops drugs that will enhance memory and brain function.
Genes, Brain and Behavior (2003)
2:
187–190 Copyright ßSaegis Pharmaceuticals, Inc. 2003
ISSN 1601-183X
187

mutagenesis (for example Ethyl Nitroso-Urea (ENU)) has
also been successfully employed to generate mutant mice
exhibiting altered behavior (Sayah et al. 2000). The analysis
of the genetic modulation of senescence of Homo sapiens
has been proposed (Martin 1996) and will be dramatically
facilitated by the sequencing of the human genome. Studies
combining transgenic and pharmacological approaches have
now been utilized to reveal more details about the mechan-
isms of learning and memory (Ohno et al. 2002). Memory
suppressor genes have been revealed in multiple organisms
from Aplysia,Drosophila to the house mouse (Cardin & Abel
1999). Proteomics is now utilized to understand how pro-
teins interact and how this interaction may modulate mem-
ory processes (Grant & Husi 2001). These are just a few of
the most promising developments.
The practical aspect of these and other discoveries is that
by now several drugs exist that can positively influence even
such complex human brain disorders as depression and anx-
iety. Computer modeling of biochemical interactions and in
silico screening for compounds will have an unprecedented
impact on drug development, both in terms of speed and
depth of knowledge. The sequencing of our own genome
and those of several model organisms will also have great
impact. It is almost certain that as a result of these new
techniques and our improving understanding of how the
brain works, our ability to modify memory to our advantage
will not stop at today’s level but will continue to improve.
Although the question of how one can precisely modulate
a complex set of biochemical pathways to achieve a
desired memory improvement is not trivial, numerous results
from the literature (see review by Iversen 1998; or an
example by Gerlai 2001) now suggests that it is not implau-
sible. According to the anecdote, Lord Kelvin once explained
that heavier-than-air flying machines are impossible.
Skeptics may feel similarly today, but more and more
problems of memory research will be solved and medical
intervention to enhance our cognitive function will be
developed.
The question of who should accept such treatments and
take ‘smart’ drugs is perhaps more problematic. The distinc-
tion between patients suffering from as devastating a
disorder as Alzheimer’s disease and persons considered
healthy may make the answer misleadingly simple: people
suffering from a well defined brain disorder associated
with memory dysfunction should take the ‘smart’ drug.
However, what was once considered a slight deviation
from normal, for example social withdrawal affecting a
negligible number of people, is now known to be autistic
spectrum disorder (ASD), a neurodevelopmental disease
representing a clearly accepted and enormous unmet
medical need (for review see Gerlai & Gerlai in press).
Perhaps age related cognitive decline (ARCD) (for example
Celsis et al. 1997) often seen in the ‘normal’ elderly, may also
not be considered part of normal human aging in the future.
What is normal anyway? Evolution ‘designed’ us to live for
about 25–30 years (for review see Kirkland 1989), a ‘normal’
life-span of Homo sapiens 10 thousand years ago. Does this
mean that we should all accept our fate and die early by
avoiding twenty-first century medical help, nutrition and tech-
nology?
Some may believe that enhancing memory or cognition
means that the memory trace will be irrevocably etched in
our brain and/or everything we hear, smell, see, etc. will be
equally encoded and stored, making our brain a wasteland of
non-interpretable junk memory traces, as Rose implies
(2002). It is certainly possible, but perhaps an unwarranted
assumption. Numerous possibilities may exist to enhance
plasticity bi-directionally. For example, enhancing the ability
of the synapse to undergo structural changes (Gerlai et al.
1999), or betterment of G-protein function in general (Neubig
& Siderovski 2002) may cut both ways, and lead to better
strengthening of some synapses and better weakening of
others as required during stimulus processing in the brain.
Thus relevant things may be learned and remembered better
and irrelevant ones ignored or forgotten faster.
Taking an evolutionary perspective, could artificial memory
enhancement be possible at all? A skeptic may argue that
the human brain is an optimally tuned system and anyone
who fools with it is destined to fail. In other words, we have
reached the top performance level and there is no room for
improvement to be achieved by evolution or by our own
technology. We know that large natural differences exist
among people in cognitive or memory performance. If the
brain is so well tuned, why does X remember things much
better than Y? Where are these differences coming from?
Quantitative genetic analyses suggest such differences have
a significant genetic component (for review see Bouchard
1998), and consequently a potentially traceable biological
origin and mechanism. Understanding these mechanisms
will hand us a key to the door leading to memory enhance-
ment. Is our brain really set by evolution at the maximum
level possibly achievable by a biological system with no more
room for improvement? It appears arrogant to believe this.
The ceiling may not exist at all. Furthermore, it is unlikely that
we will have to wait for millions of years for evolution to
break through the apparent barrier, technology will allow us
to move much faster.
Finally, consider some general thoughts about the dangers
that new discoveries may bring upon us. Proper utilization of
nuclear fission can provide clean and abundant energy, but it
can also be used to make devastating weapons. ‘Smart’
drugs may also be a double-edged sword. They can enhance
our lives but can also be abused or used in an unethical
manner. Rose (2002) warns us to be prepared for the
implications of future technological and medical advances
and forces us to start thinking about how to make the
best of them for our society. However, irrespective of the
potential dangers, the wheel of progress will continue to
turn: our fear of the future should not stop us from making
new discoveries.
Gerlai and Rose
188 Genes, Brain and Behavior (2003) 2: 187–190

Reply
Steven Rose
1
Visiting Professor, University College London and Professor
of Biology and Director, Brain and Behaviour Research Group,
Department of Biological Sciences, Open University, Milton Key-
nes MK7 6AA, UK. E-mail: S.P.R.Rose@open.ac.uk
My review article (Rose 2002), to which Gerlai responds,
focused on the present claims and future potential for
so-called ‘smart’ drugs or more formally, cognitive enhancers.
I am indeed sceptical about the efficacy of the multitude of
agents which are currently available, either by prescription
or, as so-called ‘orphan’ drugs, by purchase over the Internet.
However, there is a reasonable likelihood that more effective
agents, capable of enhancing retention of currently learned
material, will be available in the not-too-distant future, and
that the time to begin considering their ethical, social and
legal implications is now, rather than retrospectively. The
availability of such drugs will be relevant to cognitive decline
in ageing, notably Alzheimer’s disease (AD), but also raises
issues about their use in a non-clinical setting.
Gerlai rightly refers to the considerable body of evidence
concerning the molecular and cellular cascade occurring dur-
ing memory formation in experimental animals. The analysis
of this cascade has occupied me for most of my researching
life (see Rose 2000 for review). Indeed it is on the basis of
this work that we are currently developing a small peptide
that promises to restore recent memory function in AD (see
Mileusnic et al. 2000 for an initial account of this work; follow
up papers are currently in preparation). However, discussing
these processes was not relevant to my purposes in the
‘smart’ drugs review. But it is important to note that in this
field progress in moving from agents that work in animal
models to drugs that might enhance human memory has
sadly not been easy.
My review took pains to point out that memory enhance-
ment is not necessarily an unalloyed good, even for the
individual, and discussed the therapeutic and sometimes
beneficial effects of forgetting. However there is no doubt
that effective treatments for memory loss in AD would be
enormously beneficial, both for the individual in the early
stages of the disease and for carers. Sadly, we still don’t
have more than partially effective drugs at present, which is
why such an immense research effort is now being directed
towards finding better treatments, including Gerlai’s and my
own work. As to whether outside the clinical context we as a
society wish to or are able to ‘break through’ some cognitive
ceiling by genetic or pharmacological manipulation as he
suggests, remains a speculation. At the moment I feel
there are more immediately pressing issues with which we
should be concerned.
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1
The author is not affiliated with any pharmaceutical company, but is
currently in discussions about the possible pharmaceutical
development of cognition-enhancing drugs based on his work.
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