The Temporal Choreography of Memory

The hiatus on this blog was a combination of taking the GREs and pre-holiday laziness. I am, however, pleased to announce that this post and the previous one are results of my original interviews with researchers who were kind enough to give me their time and assistance.

Precious as our memories are, they are also our most fragile possessions; study after study has shown that they erode over time. This impermanence is controlled by a staggeringly complex process that neuroscientists have long been trying to comprehend. Now, researchers from New York University and the University of California, Irvine, have published research in the Proceedings of the National Academy of Sciences that uncovers a major clue to this process. They identify specific molecules that shape not only how, but where and when memories are created. Specifically, they found that two, MAPK and PKA, interact spatially and temporally in our neurons to trigger memory formation.

Team leader Dr. Thomas Carew from New York University calls this molecular interaction a kind of “temporal choreography”. His team used neurons from Aplysia californica, the California sea slug, to observe the interactions of MAPK and PKA. Humble though they may seem, sea slugs are a boon to memory research. Compared to the neurons in the human brain, which number in the order of trillions, Aplysia has about 10,000 neurons, each of which are much larger than ours, making their molecular pathways easier to study.

By stimulating the neurons in the tail of the sea slugs, the team was able to monitor when and where MAPK and PKA appeared to consolidate the memory of that stimulation. They found that PKA is crucial for both short term memory, which lasts over a single trial, and intermediate-term memory, which lasts a few hours. Long term-memory, which forms over a few days, required both MAPK and PKA. Ultimately, “we also found that MAPK’s actions are required for PKA to work,” says Dr. Carew. Even more interestingly, PKA was detected first in the synapses of neurons and then in the cell bodies, providing an important clue to both where and when memories are formed.

“MAPK and PKA are both important and we’ve known that for a while,” says Dr. Todd Sacktor, who published seminal work on how the PKMZeta protein helps create and even restore long-term memories. “How they interacted, however, was a mystery. What we especially didn’t know was whether they interacted in series, or parallel. But now through this study, we realize that they act in series in the synapse.” In terms of highlighting how the brain learns, Dr. Sacktor thinks this is “a big advance”.

Although the interactions of these two molecules helps us understand how neurons create memories, Dr. Carew acknowledges that much needs to be done to bring this research to the clinic or bedside. “We can’t just drink a quart of PKA and learn to speak Greek,” he says. The next step would be to test the behaviors of sea slugs with this model of memory formation in mind. Although the behavioral constraints of Aplysia are significant — “Let’s say they’re not getting into NYU or Yale”, is Dr. Carew’s assessment — they can be used to study the molecular level of memory creation.

Dr. Sacktor thinks the study may have even more immediate implications. “There’s been an awful lot of effort done by different labs in using PKA for cognitive enhancement,” he explains. “This study would provide them with clues on what the best way to deploy those PKA enhancers would be.”

Despite the building body of work in memory formation and retention, Dr. Carew does not believe that a silver bullet exists for memory-related diseases like Alzheimer’s or dementia. “Not all cognitive impairment is the same; the deficit in memory might look the same, but there are very different underlying mechanisms,” he explains. Instead, Dr. Carew suggests that our increasing understanding of the memory pathways will lead to targeted therapy for these ailments — and hopefully, the reduction of human suffering.

My thanks to Dr. Carew’s wonderful explanations and the press office of NYU for helping me get in touch with him. Thanks also to Dr. Sacktor, who was kind enough to give me some time on a weekend to discuss this work. 


1. The original press release by NYU on EurekAlert:


Smaller Than A Tricorder

The hiatus on this blog was a combination of taking the GREs and pre-holiday laziness. I am, however, pleased to announce that this post and the next are results of my original interviews with researchers who were kind enough to give me their time and assistance.

Once again proving that science fiction isn’t just fiction, researchers at Penn State University have taken a major step towards creating a real-life version of Star Trek’s nifty tricorder, which scans and automatically detects diseases.

Published recently in Lab on a Chip, the work done by Professor Tony Jun Huang and his team at Penn State demonstrates that a flow of leukemia cells can be diverted and sorted into more than five channels by standing acoustic waves. Other methods can manage two channels at most and the equipment can be desktop-sized; this chip could fit in your palm.

The chip uses frequencies between 9.5 MHz and 14.5 MHz, nearer to the ultrasound region than human hearing, which allows the cells to emerge from the device unscathed. Some other methods of sorting cells use magnets and lasers, but they tend to damage the cells, says Dr. Huang. He likens this chip to the ultrasound technique used for obstetric purposes, explaining, “You’d always use ultrasound to check pregnant women — not magnets!”

Two digital transducers on the chip emit surface acoustic waves, which produce pressure nodes (regions of low pressure), and anti-nodes (regions of high pressure). The cells being sorted are diverted into the pressure nodes; changing the frequencies of the transducer waves means that the distribution of the pressure nodes can be modified, too. This is how Dr. Huang’s team was able to produce different “channels” of leukemia cells.

A major advantage of this method, according to Dr. Huang, is that the cells are placed very precisely. The chip could potentially sort different kinds of white and red blood cells for further analysis, or tumor cells circulating in the bloodstream.

Disease detection, however, is still a little way into the future: while the acoustic cell sorter can divert cells into various channels, it isn’t fitted with a detection system. Calling it a Star Trek-like tricorder is therefore a little optimistic, but Dr. Huang says his team is working on this very problem.

In the meantime, companies have already come knocking. Dr. Huang mentions he’s spoken to a few since his research was published, but acknowledges the difficulties of commercializing something that’s still very experimental. “I’m thinking of starting a company myself,” he says, only half-jokingly.

A venture that creates a hand-held scanner and detector straight out of sci-fi? Sounds like a fantastic business plan.

My thanks to Dr. Huang for the time he took to explain the concepts behind his team’s achievement, and to the press office at Penn State.


1. Penn State press release via EurekAlert:


Daily Roundup: Memory Modification

The latest in the spate of memory-related findings comes from the researchers at New York University and the University of California, Irvine. We’ve seen the effects of broad protein synthesis and how the interruption of the PKMZeta enzyme can cause long-term memory loss. Spatially, we’ve also seen how neurons can be stimulated to trigger memories. And at a lower level, scientists have identified how the Npsa4 gene is crucial for consolidating memories.

Now we have a little more information about how the molecules MAPK (mitogen-activated protein kinase) and PKA (cAMP-dependent protein kinase) are responsible for memory retention. According to the press release from NYU, PKA production increases for short term memory (30 minutes) in the sea slugs (really) being studied, and MAPK enters the picture when it comes to longer term memories. Interestingly, the creation of long-term memories involves both MAPK and PKA, with the former stimulating the latter’s involvement.

The abstracts that I found describing the proteins’ behavior were written several years ago, so I’m curious about the state of the research in memory modification and recall. I’d be interested to know what the authors think about the PKMZeta enzyme and how that plays into this research.

Additional info:

1. MAPK abstract on learning:

2. PKA’s role in learning:

The 2012 Nobel Prize in Chemistry

This year’s Nobel for Chemistry is awarded to Robert J. Lefkowitz and Brian K. Kobilka for their discovery of how the G-protein-coupled receptors (GPCR) work in our cells. This might sound a little finicky, but consider that the GPCR family accounts for half of pathways targeted by medical applications that do a whole host of things, from reducing pain to providing psychiatric relief to patients.

The impression I get from the excellent popular press release from is that the Nobel was awarded to the men who found ingenious ways of not only tracking the receptors’ work, but also in capturing the first images of how the protein actually functions within the cell.

GPCRs are so crucial because they provide one of the major ways that cells within our body interact with the external environment. Many intra-cellular activities occur in response to an external stimulus. For instance, you are startled by a sudden bang and your immediate instinct is to run away — that response is a result of adrenaline flooding your system, speeding up your heart but relaxing the pupils of your eyes. When adrenaline floods the system, it enters cells through the fatty acid layer of the cell and activates proteins that then go on to produce the correct physiological responses.

Normally I’d go ahead and explain the protein actions here, but in this case, I can’t do better than to refer to the press release, which is extremely clear and written with the lay person in mind.


The 2012 Nobel Prize in Physics

This year’s Nobel has been awarded jointly to the French physicist Serge Haroche and American physicist David J. Wineland, for their independent usage of a special ultracool cavity and an ion trap respectively, to capture and study individual particles in their quantum states. This might sound extremely theoretical, but it could lead to the advancement of quantum computing, where computers can perform incredibly complicated algorithms in a fraction of the time they take to finish today.

All this is the result of the mind-bendingly odd physics that happens down at the atomic level, a quantum state that’s unlike anything we see in classical physics.

Quantum weirdness, to be honest, happens all the time: particles are naturally imbued with the ability to be both a, well, particle as well as a wave depending on how they’re measured and observed. But we don’t see cows, for instance, waving enthusiastically in fields because at the macro level these quirks of the quantum world cancel out. And they do so because of how the particles themselves interact with the external world.

In their natural, unobserved state — a sort of Platonic ideal, really — particles exist in a cloud of probable locations. They can’t really be pinned down, as Heisenberg discovered; they can be measured spatially or their velocities can be tracked, but never both simultaneously. This is said to be a superposition of states. This is where Schrodinger’s cat, poor creature, comes into the picture. The paradox, as the physicist put it, is that since every particle is in a state of flux, then so must the macro object be in flux. If you put a cat in a box, and place a dangerous radioactive isotope in it, then you essentially have three probable states once the radioactive isotope decays: the cat is dead; the cat is alive, or the cat is in a bizarre superposition of both dead and alive states. Yet when we open the box, the cat is either dead or alive, and can never be both simultaneously. Why is this so, and how did we resolve that strange paradox?

Much of the work that Wineland and Haroche have been doing centers on this very question. I don’t mean to say that they’ve solved the entire problem of what a quantum atomic particle is, or anything fundamentally philosophical* regarding the field of quantum physics, but I do know that their work has illuminated the stages by which an atom or photon resolves itself from a haze of probability into a classical particle, like a distant object comes into focus when we train a pair of binoculars onto it.

Their work is very different, yet very complementary. Here are quotes from Stockholm’s** press release package regarding the nature of Wineland’s research:

…electrically charged atoms or ions are kept inside a trap by surrounding them with electric fields. The particles are isolated from the heat and radiation in their environment by performing the experiments in vacuum at extremely low temperatures.

Actually those particles are created using a very interesting method outlined in the advanced background PDF from the Nobel website: they’re first energized by a laser, and then allowed to decay to a lower energy state — so low, in fact, that it’s close to absolute zero. Then, Wineland’s team further stimulates the atom with a laser so that it achieved something that’s halfway between two of the states that it could occupy. Left in a strange limbo between one state and another, the atom is now in a superposition of states, and its weird and wonderful properties can be studied.

In contrast, Haroche and his team created a cavity from extremely reflective superconducting glass, which contained a variable number of photons that bounced back and forth between the mirrors for an extremely long distance (a whopping 40,000 km, to be precise). To measure the presence of the photons, the team sends in very carefully prepared atoms that don’t absorb the photons but are changed by it; they undergo what’s known as a phase shift. As the press release package puts it,

…if you think of the atom’s quantum state as a wave, the peaks and the dips of the wave become shifted

Haroche’s team effectively built a nano-lab that could be used to chart the evolution of an atom as it went from a highly complex quantum state to one where it behaved essentially like a classical particle.

This could lead the way to those most magical of technologies that we’ve been dreaming about this century: a quantum computer.

*In fact, I’d be wholly unqualified to answer that.

** Only because I think saying “Stockholm” is so much cooler than saying “the Nobel committee”

The 2012 Nobel Prize in Physiology or Medicine

Yesterday, the Nobel committee in Stockholm announced that the 2012 Prize in Physiology or Medicine would be going to John B. Gurdon and Shinya Yamanaka for the discovery that adult, differentiated cells could be de-differentiated again into pluripotent cells.

In countries where research on embryonic stem cells is essentially frozen — like Japan, for instance — this variety of pluripotent cells could prove to be a boon. More importantly, experiments done by these men revolutionized our understanding of the cellular lifecycle; no longer was it unidirectional, where cells moved down a one-way path into specialization.

I especially liked SciAm’s profile of Yamanaka’s work. His research showed that a bare handful of genes — four, to be precise — could turn back cellular time and ‘regress’ the cell into its pluripotent state.

…[Yamanaka]uncovered 24 factors that, when added to ordinary mouse fibroblast cells and subjected to the correct culturing procedures, could create pluripotent cells virtually identical to stem cells. Yamanaka kept examining each factor and found that none could do the job alone; instead a combination of four particular genes did the trick.

Note the “virtually identical” in that paragraph.

Yamanaka and others do not think that iPS cells can replace their embryonic counterparts yet. “We don’t yet know if embryonic stem cells and iPS cells are truly equivalent,” says Konrad Hochedlinger of Massachusetts General Hospital’s Center for Regenerative Medicine.

There are other issues with pluripotent cells: they need to be injected with some kind of retrovirus, which would leave the new cells full of the potential to attack our immune system. They’ve been working on this, however, and now Yamanaka’s team has come up with a way to use a circular, double stranded round of DNA called plasmids to replace retroviruses.

Yamanaka’s lab reported success using plasmids, or circular pieces of DNA. Other retrovirus alternatives include proteins and lipid molecules.

The risks don’t end there. Since one of the genes that controls the induction of pluripotency is strongly cancerous, there’s a chance that the stem cells could become tumorous too. There’s still hope, though:

…the transcription factor c-Myc happens to be a powerful cancer gene, and the cells produced by Yamanaka’s team tended to become cancerous. “Making iPS cells is very similar to making cancer,” he explains. In principle, c-Myc may not be necessary: in mice, Yamanaka and a group led by Rudolf Jaenisch at the Massachusetts Institute of Technology found a way to avoid using c-Myc, in part, by optimizing culture conditions.



Daily Roundup: Dissolving Circuits

Most ideas of bio-electrical fusion come in the form of cybernetics or nano robotics, devices that either supplant our limbs and organs or tiny monitoring creatures that patrol our biological pathways. Although both have been researched, the recent invention and demonstration of soluble electronic circuits by researchers from Tufts University, Northwestern University and the University of Illinois might hold more immediate and efficient promise of a bioelectric future.

As this Smithsonian article explains, silicon naturally does dissolve in water, but there’s simply too much of it in traditional circuitry which is dense with the material. Instead of taking years of dissolve, however, this silk-coated, transparent film of circuitry that the researchers have come up with dissolves upon contact with water and can be tuned to melt away with different “shelf lives” as it were.

One of the more truly astonishing things the researchers have created includes a 64 pixel camera. We can imagine it would be incredibly useful trundling down blood vessels or the digestive tract and providing real-time diagnostics of a patient’s well-being.

I’m most interested now in how these circuits became a) ultra thin and clear (and if the latter has any significant advantage), and b) how the circuits were printed. The article mentions soluble conductors like magnesium and magnesium oxide, but the article would’ve been more complete with a better explanation of the process if it was different from the traditional method of manufacturing.

Still, it would be fascinating to see the applications of such material in the future. Imagine them being sold as simple consumer monitoring and fitness products, which can keep track of heart rate and/or hormone levels to give us feedback on how we’re treating our bodies.