Moncrieff: 355-365; Patterson: 240-248
by Dennis Abrams
“The cruel discovery which I had just made could not be of service to me so far as the actual material of my book was concerned. For I had decided that this could not consist uniquely of the full and plenary impressions that were outside time…I should pay particular attention to those changes which the aspect of living things undergoes, of which every minute I had fresh examples before me…” “The process of ageing, I found, was not marked in them all by signs of the same sort.” M. de Cambremer. “Do you still have your fits of breathlessness?” “…I saw he had been made unrecognisable by the attachment of enormous red pouches to his cheeks which prevented him from opening his mouth or his eyes completely…” The breathlessness of M. de Cambremer’s sister had declined with age, why hadn’t Marcel’s? Mme de Cambremer-Legrandin does not see what has happened to her husband’s face: “She had not noticed the disfigurement which offended my eyes and which was merely one of the masks in the collection of Time, a mask which Time has fastened to the face of the Marquis, but gradually, adding layer to layer so slowly that his wife had perceived nothing.” “And now I was beginning to discover that, in the appreciation of the passage of time, the first step is the hardest.” How can so much time have elapsed is followed by how can the lapse have been so slight. “Within a few minutes I had developed, though very much more rapidly, in the same fashion as those who, after finding it hard to believe that somebody they knew in their youth had reached the age of sixty, are very much more surprised fifteen years later to learn that the same person is still alive and is only seventy-five.” M. de Cambremer’s mother “She is wonderful still.” More color and makeup for women, less color for men. Legrandin, “with his long-drawn and gloomy features he was like some Egyptian god. Or perhaps less like a god than a ghost.” “Others again had preserved their faces intact and seemed merely to walk with difficulty; at first one supposed that they had something wrong with their legs; only later did one realise that age had fastened its soles of lead to their feet.” “I marveled at the power to renew in fresh forms that is possessed by Time, which can thus, while respecting the unity of the individual and the laws of life, effect a chance of scene and introduce bold contrasts into two successive aspects of a single person…Time, the artist, had made all the sitters portraits that were recognizable; yet they were not likenesses, and this was not because he had flattered them, but because he had aged them.” Time works slowly. Odette and Gilberte. Ski. Aging turns some into adolescents: “They were not old men, they were very young men in an advanced stage of withering.” Old age has made some men and women “whom I remembered as unendurable and who had now, I found, lost almost every one of their defects, possibly because life, by disappointing or by gratifying their desires, had rid them of most of their conceit or their bitterness.” Mme d’Arpajon, “seemed to me at the same time unknown and familiar…It was the appearance, often seen by me in the course of my life, of certain stout, elderly women, of whom at the time I had never suspected that, many years earlier, they could have looked like Mme d’Arpajon.”
Quite a portrait gallery and analysis of the many ways of aging…so much for me to look forward to.
For your weekend pleasure, I’d like to continue the section from Jonah Lerner’s Proust was a Neuroscientist, discussing the work of Dr. Kausik Si to identify the reasons why memory endures.
“Si began his search by thinking through the problem. He knew that any synaptic marker would have to be able to turn on messenger RNA (mRNA), since mRNA helps make proteins, and new memories need new proteins. Furthermore, because mRNA is regulated where memories are regulated — in the dendrites — activating mRNA would allow a neuron to selectively modify its details. This insight led Si to frog eggs. He had heard of a molecule that was able to activate specific scraps of mRNA during the egg’s development. This same molecule also happened to be present in the hippocampus, the brain’s memory center. Its ignominious name was CPEB, for cyptoplasmic poplyadenylation element binding protein.
To see if CPEB was actually important for memory (and not just for frog zygotes), Si began by searching for it in purple sea slugs, a favorite experimental animal among neuroscientists. To his pleasant surprise, CPEB was present in the slug’s neurons. Furthermore, CPEB was present precisely where a synaptic marker should be, silently skulking in the dendritic branches.
Si was now intrigued. He began his quest to understand CPEB by blocking it. If CPEB was removed, could the neuron still make a memory? Could the cell still mark a synapse? Though he hardly believed his own data, the answer was clear: without CPEB, the slug’s neurons were unable to remember anything.
But he still couldn’t figure out how CPEB worked. How did this molecule exist outside time? What made it so strong? How did it survive the merciless climate of the brain? Si’s first clue arrived when he decoded the protein’s amino acid sequence. Most proteins read like a random list of letters, their structures a healthy mix of different amino acids. CPEB however, looked completely different. One end of the protein had a weird series of amino acid repetitions, as if its DNA had had a stuttering fit (Q stands for the amino acid glutamine):
Immediately, Si began looking for other molecules with similar odd repetitions. In the process he stumbled into one of the most controversial areas of biology. He found what looked like a prion.
Prions were once regarded as the nasty pathogens of a tribe of the worst diseases on earth: mad cow disease, fatal familial insomnia (whose victims lose the ability to sleep, and after three months die of sleep deprivation), and a host of other neurodegenerative diseases. Prions are still guilty of causing these horrific deaths. But biologists are also beginning to realize that prions are everywhere. Prions are roughly defined as a class of proteins that can exist in two functionally distinct states (every other protein has only one natural state). One of these states is active and one is inactive. Furthermore, prions can switch states (turn themselves on and off) without any guidance from above; they change proteomic structure without changing DNA. And once a prion is turned on, it can transmit its new, infectious structure to neighboring cells with no actual transfer of genetic material.
In other words, prions violate most of biology’s sacred rules. They are one of those annoying reminders of how much we don’t know. Nevertheless, prions in the brain probably hold the key to changing our scientific view of memory. Not only is the CPEB protein sturdy enough to resist the effects of the clock — prions are famous for being virtually indestructible — but it displays an astonishing amount of plasticity. Free from a genetic substrate, CPEB prions are able to change their shapes with relative ease, creating or erasing a memory. Stimulation with serotonin or dopamine, two neurotransmitters that are released by neurons when you think, changes the very structure of CPEB, switching the protein to its active state.
After CPEB is activated, it marks a specific dendritic branch as a memory. In its new conformation, it can recruit the requisite mRNA needed to maintain long-term remembrance. No further stimulation or genetic alternation is required. The protein will patiently wait, quietly loitering in your synapses. One could never eat another madeleine, and Combray would still be there, lost in time. It is only when the cookie is dipped into the tea, when the memory is summoned to the shimmering surface, that CPEB comes alive again. The taste of the cookie triggers a rush of neurotransmitters to the neurons representing Combray, and, if a certain tipping point is reached, the activated CPEB infects its neighboring dendritics. From this cellular shudder, the memory is born.
But memories, as Proust insisted, don’t just stoically endure; they also invariably change. CPEB supports Proust’s hypothesis. Every time we conjure up our pasts, the branches of our recollections become malleable again. While the prions that mark our memories are virtually immortal, their dendritic details are always being altered, shuttling between the poles of remembering and forgetting. The past is at once perpetual and ephemeral.
This rough draft of a theory has profound implications for the neuroscience of memory. First of all, it’s proof that prions are not some strange biological apocrypha. In reality, prions are an essential ingredient of life and have all sorts of intriguing functions. Swiss scientists, following up on Dr. Si’s research, have even discovered a link between the prion gene that causes mad cow disease and increased long-term memory. Essentially, the more likely your neurons are to form misfolded prions, the better your memory is. Other experiments have linked a lack of CPEB in the mouse hippocampus to specific deficits in long-term memory. Though the details remain mostly obscure, there seems to be a deep connections between prions and remembrance.
But the CPEB model also requires that we transform our metaphors for memory. No longer can we imagine memory as a perfect mirror of life. As Proust insisted, the remembrance of things past is not necessarily the remembrance of things as they were. Prions reflect this fact, since they have an element of randomness built into their structure. They don’t mind fibbing. While CPEB can switch to an active state under a given set of experimental circumstances (like a few puffs of serotonin), Si’s experiments also show that the protein can become active for no real reason, since its transformation is largely dictated by the inscrutable laws of protein folding and stoichiometry. Like memory itself, CPEB delights in its contingency.
This indeterminacy is part of CPEB’s design. For a protein, prions are uniquely liberated. They are able to ignore everything from the instructions of our DNA to the life cycles of our cells. Though they exist inside us, they are ultimately apart from us, obeying rules of their own making. As Proust said, ‘The past is hidden…in some material object of which we have no inkling.”
And though our memory remains inscrutable, the CPEB molecule (if the theory is true) is the synaptic detail that persists outside time. Dr. Si’s idea is the first hypothesis that begins to explain how sentimental ideas endure. It is why Combray can exist silently below the surface, just behind the curtain of consciousness. It is also why Marcel remembers Combray on page 58, and not on page 1. It is a molecular theory of explicit memory that feels true. Why? Because it embraces our essential randomness, because prions are by definition unpredictable and unstable, because memory obeys nothing but itself. This is what Proust knew: the past is never past. As long as we are alive, our memories remain wonderfully volatile. In their mercurial mirror, we see ourselves.”
I can’t help but think that Proust would be fascinated by this.
The Weekend’s Reading:
Moncrieff: Page 365-396 “The transformations effected, in the women particularly…” through “…which she, Oriane, had not taken the trouble to attend.” Kindle locations: 4672-79/5062-68
Patterson: Page 248-269 “The transformation which white hair and other factors had effected…” through “…the ones which Oriane had not taken the trouble to attend.” Kindle locations: 4498-4505/4852-59
Enjoy. And enjoy your weekend.