Another
example of molecule mythology involves a protein called PKMzeta. Some
neuroscientists have suggested that PKMzeta has the ability to make
memories last for decades in synapses, even though the proteins that
make up synapses are very short-lived (having an average lifetime of
two weeks or less). Quite a few of the papers or posts spreading this idea were written or co-written by the same person, Todd C. Sacktor. It is never explained clearly how a protein
molecule could perform this great feat of magic. For anyone to
explain such a thing clearly, he would first need to have a clear
theory of how conceptual memories and episodic memories could be
stored in synapses. No neuroscientist has ever presented a clear and
explicit theory of any such thing. Neuroscientists merely vaguely
tell us that somehow memory storage in a brain occurs through
“synapse strengthening,” without presenting any clear theory of
how that could occur.
Of
course, if you do not have a clear theory of how memories could be
stored (for even a few minutes) in synapses, you cannot possibly have
a clear theory as to how some protein molecule such as PKMzeta could
possibly cause memories stored in synapses to persist for decades,
even though the proteins that make up such synapses are very
short-lived, lasting an average of less than two weeks. Trying to
defend against the charge that synapses are totally unsuitable for
storing memories for decades, because of the short lifetimes of the
proteins
that make up synapses, a scientific paper states, “As long as PKMZ
[PKMzeta] remains active and there is an absence of forces which
terminate its activity (such as LTD), it will continue to sustain the
biochemical changes at the synapse which serve as the neurobiological
basis of memory, allowing the memory to persist for durations far
exceeding the turnover of its component molecules.” But how could
such a miracle of persistence occur, which would be like a message
written in wet sand at the seashore persisting for decades, even
though the wet sand was being replaced and written over whenever the
tide came in? The science paper does not tell us.
Again,
we have the case of an “action verb” inappropriately used to
describe a molecule. We are told that PKMzeta has a “sustain”
super-power allowing it to preserve fantastically complicated
information supposedly stored externally in synapses made up of short-lived molecules
that are constantly being replaced. There is nothing in the
structure of PKMzeta that should cause us to believe it can do any such thing. No theorist has presented an explicit theory as to how anything like PKMzeta could preserve a memory. Such theorists may sometimes present chemical details to impress us, but such details do not constitute a theory unless a theorist gives explicit examples of precisely how specific memories (such as someone's memory of seeing Paris or someone's memory of details learned about World War I) could be permanently stored with the aid of PKMzeta. No theorist has done any such thing.
I suppose that if a PKMzeta molecule were able to cause memories to persist despite rapid protein turnover, we might imagine it as some kind of "genius" molecule that has thoughts like this:
Oh, my goodness, I see that a memory is starting to degrade because of protein turnover! The memory now states, "Ottawa is the capitol of," which isn't even a full English sentence. Why, I'd better synthesize some new proteins to fill in for those proteins that died, so there can be a nice complete English sentence. Now, what was that country that Ottawa is the capital of?
Of course, anything the slightest bit like this is very hard to believe in. It would seem that the most minimal requirements that a molecule would have to fulfill in order to be a "memory maintenance molecule" would be the following:
(1) The molecule would have to somehow know whenever a particular protein molecule (that was part of a memory stored in a synapse) had died or disappeared because of the short lifespans of protein molecules.
(2) The molecule would have to somehow cause a replacement protein of the same type to appear in the same place as the vanished molecule, so that the memory did not degrade.
The problem is that no one can envision a credible scenario under which a molecule could have either of these powers. To imagine how much of a miracle it would be for memories to persist despite constant protein turnover, you can imagine a homeowner with ten picnic tables in his backyard, each of which is filled with leaves on which a word or two is written. Imagine these leaves spell out narratives, factual information, and ideas. But the problem is that about one day in three there are winds blowing the leaves off of the tables, and scattering them far away. Also, the leaves don't last longer than a year, because they tend to crumble. Now imagine the homeowner has to keep all this information preserved in the leaves, not just for a few nights but for 50 years. That would be a mountainous job. An equally mountainous job would have to be done if memories were to be preserved in brains despite constant protein turnover causing proteins to persist an average of less than two weeks, and no one has explained how a molecule could possibly do such a feat. Since synapses face not only rapid protein turnover inside them but also the problem that synapses don't last for longer than a year or two, they have the same "double degradation" problem that such a homeowner would have with his information written on leaves.
In the article here, a PKMzeta enthusiast is asked to explain how PKMzeta could cause memories to persist. The scientist gives a lengthy answer which fails to explain how PKMzeta could do such a thing. He merely says "a cluster of PKMzeta molecules can keep themselves turned on perpetually," and then claims that this supposed ability "is a plausible mechanism for memory persistence," without justifying that claim. This fragmentary theorizing is just hand waving. It has never been demonstrated that any cluster of PKMzeta molecules is capable of storing any information (such as a list of words) for a period as long as a month. We can imagine hypothetical lab experiments that might try to show such a thing, but they have never been done. The paper here refers to "900 synaptic proteins." PKMzeta is only one of those 900 proteins in synapses, being no more common in synapses than an average synapse protein. You don't solve the "short lifetime of proteins" problem by trying to argue that one in 900 of those proteins might somehow have some stability. As for the scientist's use of the word "plausible," it has been noted by others that "plausible" is the most abused word in theoretical science discourse, and that scientists often carelessly use the word "plausible" without ever doing anything at all to show a likelihood.
I suppose that if a PKMzeta molecule were able to cause memories to persist despite rapid protein turnover, we might imagine it as some kind of "genius" molecule that has thoughts like this:
Oh, my goodness, I see that a memory is starting to degrade because of protein turnover! The memory now states, "Ottawa is the capitol of," which isn't even a full English sentence. Why, I'd better synthesize some new proteins to fill in for those proteins that died, so there can be a nice complete English sentence. Now, what was that country that Ottawa is the capital of?
Of course, anything the slightest bit like this is very hard to believe in. It would seem that the most minimal requirements that a molecule would have to fulfill in order to be a "memory maintenance molecule" would be the following:
(1) The molecule would have to somehow know whenever a particular protein molecule (that was part of a memory stored in a synapse) had died or disappeared because of the short lifespans of protein molecules.
(2) The molecule would have to somehow cause a replacement protein of the same type to appear in the same place as the vanished molecule, so that the memory did not degrade.
The problem is that no one can envision a credible scenario under which a molecule could have either of these powers. To imagine how much of a miracle it would be for memories to persist despite constant protein turnover, you can imagine a homeowner with ten picnic tables in his backyard, each of which is filled with leaves on which a word or two is written. Imagine these leaves spell out narratives, factual information, and ideas. But the problem is that about one day in three there are winds blowing the leaves off of the tables, and scattering them far away. Also, the leaves don't last longer than a year, because they tend to crumble. Now imagine the homeowner has to keep all this information preserved in the leaves, not just for a few nights but for 50 years. That would be a mountainous job. An equally mountainous job would have to be done if memories were to be preserved in brains despite constant protein turnover causing proteins to persist an average of less than two weeks, and no one has explained how a molecule could possibly do such a feat. Since synapses face not only rapid protein turnover inside them but also the problem that synapses don't last for longer than a year or two, they have the same "double degradation" problem that such a homeowner would have with his information written on leaves.
In the article here, a PKMzeta enthusiast is asked to explain how PKMzeta could cause memories to persist. The scientist gives a lengthy answer which fails to explain how PKMzeta could do such a thing. He merely says "a cluster of PKMzeta molecules can keep themselves turned on perpetually," and then claims that this supposed ability "is a plausible mechanism for memory persistence," without justifying that claim. This fragmentary theorizing is just hand waving. It has never been demonstrated that any cluster of PKMzeta molecules is capable of storing any information (such as a list of words) for a period as long as a month. We can imagine hypothetical lab experiments that might try to show such a thing, but they have never been done. The paper here refers to "900 synaptic proteins." PKMzeta is only one of those 900 proteins in synapses, being no more common in synapses than an average synapse protein. You don't solve the "short lifetime of proteins" problem by trying to argue that one in 900 of those proteins might somehow have some stability. As for the scientist's use of the word "plausible," it has been noted by others that "plausible" is the most abused word in theoretical science discourse, and that scientists often carelessly use the word "plausible" without ever doing anything at all to show a likelihood.
But
the PKMzeta enthusiasts have done a few studies which they claim
lends credibility to their claims. I will describe a typical such
study. A small number of mice are injected with something that
suppresses the PKMzeta molecules in their body (or perhaps they are
genetically engineered so that they don't have any PKMzeta). Memory
experiments are then done. It is sometimes found that such mice
perform not as well as normal mice. Such experiments have been hailed
as support for the “memory maintenance” claims about PKMzeta.
There
are several reasons why such studies do not at all show the claims
about PKMzeta are correct. The first is that a result such as I
described could never show that PKMzeta can save memories from
destruction for years. Whenever memory is tested, it's hard to figure
out what the cause is for a discrepancy between two test groups. A difference in a test
result might be because (1) PKMzeta is involved in perceiving
whatever observation is being tested; (2) or that PKMzeta is involved in
memory storage; (3) or that PKMzeta is involved in memory retrieval; (4) or that PKMzeta has something to do with attention or focus used in a memory test. A
test discrepancy could never tell us which of these things was
involved. And if some mice did worse in remembering things without
PKMzeta, that might justify the small claim that PKMzeta has
something to do with memory, but could never justify the vastly more
extravagant claim that PKMzeta is capable of preserving memories for
decades.
Another
reason why such studies do not at all show the claims about
PKMzeta are correct has to do with a general malaise in
neuroscience. A general problem in modern neuroscience is the
production of papers with marginal results that we cannot trust
because of things such as small sample sizes and publication bias.
Let us imagine that neuroscientists want to prove some idea that fits
in with their ideological expectations. A great number of
experiments might be done, almost all producing no support for the
idea. But perhaps
1 in 20 might produce results marginally supporting the idea,
probably because of chance variations in data. Now, today negative
results are vastly less likely to get published than positive
results. So if 19 researchers get a negative result, conflicting with
what neuroscientists hope to get, it could be that 10 of them don't
even bother to write up their results as a scientific paper, and that
the other 9 do write up a paper but don't get it published (because
of the journal bias against negative results). However the one
researcher who (by chance) got a positive result will write up his
result as a scientific paper. Since it will be a result neuroscientists were hoping
to get, he will almost certainly get the result published.
This
publication bias is a great problem affecting the reliability of
scientific research. Because of it we should follow a precautionary neuroscience rule like this: don't
believe something has been established unless the result turns up fairly consistently at a high level of significance, in studies with large
sample sizes.
Has
this happened in regard to memory experiments involving PKMzeta? Not
at all. In 2011 a scientist reported three separate studies showing that inhibiting PKMzeta has no effect on memory if tested between 10 and 15 day after the memory forms. In 2013 two groups of scientists published results
conflicting with claims that PKMzeta might allow memories to persist
a long time. One study by a team of scientists used genetically
engineered mice that had no PKMzeta. It found that such mice “have
no deficits in several hippocampal-dependent learning and memory
tasks,” and concluded that PKMzeta is not required for memory or
learning. Another study by a different team of scientists found that
absence of PKMzeta “does not impair learning and memory in mice.” A 2015 study found that inhibiting PKMzeta has no effect on memory in tests performed 30 days after the memory forms. A 2016 paper also found that that inhibiting PKMzeta has no effect on memory in tests performed 30 days after the memory forms.
Such
studies would seem to completely debunk claims that PKMzeta enables
memories to persist for decades in synapses despite the short
lifetimes in the proteins.
The
SUNY scientists such as Sacktor who helped to spread the PKMzeta myth have tried to
fight back with papers such as this 2016 paper. But in that very
paper we see evidence that second-rate science is being used to try
to prop up claims about PKMzeta. In Figure 7 the scientists tell us
how many mice were used for their experiment involving the memory
effects of PKMzeta deprivation. They used only 8 mice per study
group. That's way too small a sample size to get a moderately
convincing result. It is well known that at least 15 animals per
study group should be used to get a moderately convincing result. If
you use only 8 animals per study group, there's a very high chance
you'll get a false alarm, in which the result is due merely to chance
variations rather than a real effect in nature. In fact, in her post "Why Most Published Neuroscience Studies Are False," neuroscientist Kelly Zalocusky suggests that neuroscientists really should be using 31 animals per study group to get a not-very-strong statistical power of .5, and 60 animals per study group to get a fairly strong statistical power of .8. Compare these numbers to the 8 animals per study group mentioned in Figure 7 of the Sacktor paper.
This
is the same “too small sample size” problem (discussed here) that plagues very many or most neuroscience experiments involving animals.
Neuroscientists have known about this problem for many years, but
year after year they continue in their errant ways, foisting upon the
public too-small-sample-size studies with low statistical power that don't prove anything
because of a high chance of false alarms.
If you look up the PRKCZ gene behind the PKMZeta protein molecule, using this page and this page of the Human Protein Database, you will find no characteristics that seem unusual, and nothing suggesting any superstar status. The pages make no mention of the gene even being used in synapses, telling us that the gene is "mainly localized to the cytosol" and "in addition localized to the plasma membrane." The very idea of some kind of "superstar protein" or "superstar gene" is contrary to the experience in recent decades of scientists, who have found in general that bodily functions almost always involve the coordinated ballet of very many different genes (typically hundreds of them to accomplish a particular task).
If you look up the PRKCZ gene behind the PKMZeta protein molecule, using this page and this page of the Human Protein Database, you will find no characteristics that seem unusual, and nothing suggesting any superstar status. The pages make no mention of the gene even being used in synapses, telling us that the gene is "mainly localized to the cytosol" and "in addition localized to the plasma membrane." The very idea of some kind of "superstar protein" or "superstar gene" is contrary to the experience in recent decades of scientists, who have found in general that bodily functions almost always involve the coordinated ballet of very many different genes (typically hundreds of them to accomplish a particular task).
The
2015 scientific paper here shows that PKMzeta rapidly degrades in
synapses. The authors say that therefore a stable amount of PKMzeta "would be difficult to maintain at synapses and store memories over long time scales." The paper tells us “There is growing evidence against a role
for PKMzeta in memory.” Figure 9 of the paper also shows that a kind of cousin molecule or "isoform" of PKMzeta (PKC lambda) also quickly degrades, experiencing a 50% loss or degradation every 10 hours. So it seems that there is no truth to the
idea of PKMzeta (or PKC lambda) as some magic bullet that allows memories to persist
for decades in synapses that are constantly having their proteins
replaced.
Where
does that leave neuroscientists? It leaves them without a leg to
stand on in their claims that memories are stored in brains. Based on
everything we know about synapses, there is no reason to believe that
synapses are capable of storing a memory for even a month, let alone
the 50 years that is how long older humans can remember things. As discussed here and here, equally grave problems prevent scientists from creating any credible account of how memories could be encoded into neural states or how seldom-retrieved facts learned many years ago could be instantaneously recalled from a brain that seems to lack any capability for fast look-ups from exact neural positions. We also know (as discussed here and here) that massive damage can occur to brains (such as surgical removal of half of a brain) while producing little effect on memory, which would seem to be impossible if memories are stored in brains. How long before we realize that human memory cannot be a neural thing, but must be a psychic or spiritual phenomenon?
Postscript: Some people tell tall tales about the protein CAMKII similar to the tall tales told about PKMZeta. We are sometimes told that some alleged autophosphorlyation of CAMKII can help explain stable memories. Most of the reasons I have cited against PKMZeta also apply with equal strength to CAMKII. At this link we are told an experiment debunked the idea that autophosphorlyation of CAMKII has a role in memory storage. The lifetime of a CAMKII molecule is only 30 hours, according to this source. The book here makes this statement:
Postscript: Some people tell tall tales about the protein CAMKII similar to the tall tales told about PKMZeta. We are sometimes told that some alleged autophosphorlyation of CAMKII can help explain stable memories. Most of the reasons I have cited against PKMZeta also apply with equal strength to CAMKII. At this link we are told an experiment debunked the idea that autophosphorlyation of CAMKII has a role in memory storage. The lifetime of a CAMKII molecule is only 30 hours, according to this source. The book here makes this statement:
In
the mid-1980's there was much excitement about the idea that
autophosphorlyated CaMKII might serve as a self-perpetuating signal
that could subserve permanent memory storage. However, a variety of
experimental results generated since then suggests that perpetual
activation of CaMKII does not occur with LTP-inducing stimulation or
memory storage.
This
scientific paper says the following:
Previous
models have suggested that CaMKII functions as a bistable switch that
could be the molecular correlate of long-term memory, but experiments
have failed to validate these predictions....The
CaMKII model system is never bistable at resting calcium
concentrations, which suggests that CaMKII activity does not function
as the biochemical switch underlying long-term memory.
This recent scientific paper says on page 9, "Overall, the studies reviewed here argue against, but do not completely rule out, a role for persistently self-sustaining CaMKII activity in maintaining" long term memory.
Post-Postscript: Those who have studied the history of science are familiar with epicycles, a complicated speculation that was introduced into Ptolemy's theory of astronomy, to try to fix cases in which the theory did not match observations. We may say these CaMKII speculations and PKMZeta speculations are epicycles intended to fix the failing synaptic theory of memory storage. But while the Ptolemaic epicycles were exact speculations, the CaMKII speculations and PKMZeta speculations are very vague, failing to specify any exact theory of memory storage.
This recent scientific paper says on page 9, "Overall, the studies reviewed here argue against, but do not completely rule out, a role for persistently self-sustaining CaMKII activity in maintaining" long term memory.
Post-Postscript: Those who have studied the history of science are familiar with epicycles, a complicated speculation that was introduced into Ptolemy's theory of astronomy, to try to fix cases in which the theory did not match observations. We may say these CaMKII speculations and PKMZeta speculations are epicycles intended to fix the failing synaptic theory of memory storage. But while the Ptolemaic epicycles were exact speculations, the CaMKII speculations and PKMZeta speculations are very vague, failing to specify any exact theory of memory storage.
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