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FEATURE 3

Memory Pharmaceuticals
How a Nobelist's Work with Sea Slugs Will Help Us Treat Alzheimer's, Parkinson's, Senility, and Down Syndrome

by Pamela Weintraub


Feature Three

Posted March 30, 2001  Issue 99


Abstract

The lowly sea slug has provided important clues about the molecular mechanisms involved in memory formation. Memory Pharmaceuticals hopes to develop memory drugs that will restore this process in people afflicted with Alzheimer's and other diseases as well as garden-variety senility.


My grandmother, age 20, took a boat to America in the early 1900s to escape the Russian pogroms, losing her new husband to pneumonia along the way. Arriving with one small child, she married a widower and resentfully raised his brood of six. Sixty years later, dying in the hospital, she looked around. Her own son, brimming with anger at the turbulence of his childhood, refused to visit her deathbed, and her stepchildren - who viewed her dispassionately - were all that remained. "Oh, what a happy family we were," she exclaimed to the skeptical group around her and promptly died. Her final bliss was distressing - had she survived pogroms and love tragically lost, the insult of poverty, and the enmity of her child, only to wind up like this? It was not a life I would wish on anyone, but it was deeply felt, and, after all, it was hers. That she could not, in the end, recall it was the final insult.

What causes us to lose our memory?

Yet about 60 percent of those who live long enough may suffer a similar fate. That is the percent of the population carrying the genes involved in age-related cognitive impairment and senility. Should those individuals live to their eighties or nineties, they may do so without the ability to retain new information or recall what transpired before. And they are just one group to suffer the ravages of memory loss - those with Parkinson's disease, those who suffered strokes or traumas to the head, and especially those with Alzheimer's disease are likely to lose the ability to create new memories or to access old ones. People diagnosed with clinical depression are at risk as well. Most people do not realize that even when the depression itself has been effectively treated with antidepressant medication, a concomitant deficit in learning and memory still remains.

What is memory, and what causes us to lose it? Those are the questions posed by researchers at the New Jersey-based Memory Pharmaceuticals, whose drug pipeline includes a host of potential treatments for Alzheimer's disease, senility, and numerous other causes of memory loss. "Our mission is to create new treatments for individuals with learning and memory-related disorders," explains Axel Unterbeck, one of the cofounders and chief scientific officer. "This is a very large and diverse patient population that grows ever larger as the baby boom generation turns gray."

World-Class Pedigree

Kandel asked the profound questions.

While Memory Pharmaceuticals has been in business just a couple of years, its pedigree is impressive. Started out of the Center for Neurobiology and Behavior at Columbia University Health Sciences, Memory Pharmaceuticals' foundation rests on work done by Nobel laureate Eric Kandel. Back in the 1950s, while still a medical student, Kandel considered becoming a psychoanalyst. Of all the medical specialties, he felt, psychiatry was the most fascinating. Who are we, and what motivates us? Why do we, each in our own way, assume a specific identity and sense of self? How do we come to embrace the same continuity of consciousness from our first days to our last?

The answers, he supposed, lay in the accretion of early experience and the memories formed in the process. When distorted by experiences that were painful, unhealthy, or inappropriate, memories - conscious or unconscious - interfere with function. Psychoanalysis, the talking cure, aims to rejigger those memories through therapy. But what is really happening as the talk therapy takes place? Can we reduce memory and learning to a series of biochemical reactions? In what some might consider the ultimate form of reductionist thinking, Kandel asks whether we might find the essence of the mind in the molecular cascades of the brain.

Every thought, every emotion is a biological process.

While colleagues have often protested against a reductionist approach to neuroscience, in which the brain is understood as a set of stepwise reactions, Kandel perseveres. "The central problem in neuroscience is to understand the cognitive functions of the human mind: perception, action, emotion, language, learning, and memory," Kandel says today. "Every thought we think, every emotion we feel is a biological process that involves the brain."

The Search for Memory

In their quest for the roots of memory, scientists wonder if they could pinpoint the phenomenon in the brain. What are the categories of memory? Where in the brain is memory actually stored and how? One clue comes from Canadian neuroscientist Brenda Milner who, in 1957, reported on the remarkable patient H.M. To alleviate epileptic seizures, H.M. was treated with surgery to the medial temporal lobe of his brain. The surgery successfully eliminated the seizures, but caused another devastating problem. H.M. now suffered profound impairment to recent memory. While he remembered places and events from the past as precisely as ever, and while his IQ had, if anything, increased, he could not recall what he had for breakfast, find his way around the hospital, or recognize members of the hospital staff. In fact, his life following surgery did not contribute to his store of knowledge at all. He was able to hold immediate impressions in his mind, but once his attention was diverted, those impressions were lost.

Not all memory is conscious.

H.M. did not lose the ability to form all new memories, it turned out, just those he could remember consciously - what researchers call "declarative" or "explicit" memory, involving recollection about facts and events. H.M.'s nondeclarative memory, which involves motor skills or visual recognition, was not at all impaired. In fact, although he had no conscious recollection of certain pictures or activities he'd been "primed" with by researchers, that priming was as helpful in improving his performance as it would be if he had no brain deficit at all.

Studies of H.M. and other amnesiac patients suggest the presence of multiple memory systems throughout the brain's many pathways. Conscious recollection is just one of many categories. Memory can be short term, lasting just seconds, or long term, lasting months or years.

Listening to the Hippocampus

The hippocampus handles long-term memories.

Looking for the source of conscious memory, researchers gleaned their best clues from the population of patients with memory deficits traced to known lesions in the brain. Overwhelmingly, the scientists found these lesions in the hippocampus, the sea-horse-shaped organ in the midbrain. Like H.M., these individuals were unable to form long-term memories, even though long-term memories formed before the brain damage remained entirely intact. The likely explanation - long-term memories are somehow processed by the hippocampus prior to permanent storage in the brain.

To shed light on this "filing system," Matthew Wilson in the Department of Biology at Massachusetts Institute of Technology and Bruce McNaughton of the Department of Psychology at the University of Arizona studied mice. They found when a mouse enters a new environment, groups of nerve cells in its hippocampus fire off electrical signals, the patterns varying with the environment itself. Then, during the night, as the mouse sleeps, the whole process is repeated, with exactly the same nerve cells firing in just the same way. It is through this process, Wilson and McNaughton explain, that experiences stored in the hippocampus during the day are permanently archived in the cortex at night. Listening to the hippocampus, the cortex, the seat of higher thought and learning, fires in a corresponding pattern. Like the random access memory in a computer, the hippocampus is a temporary holding well where memory is processed before being stored in the hard drive of the cortex.

Which memories make it into long-term storage?

Which memories make it into the archives and which are relegated to the brain's trash bin, never to be seen again? One criterion is repetition; another is the intensity of the event. After President John F. Kennedy's assassination, for instance, psychologists observed the phenomenon of "flashbulb memories," in which it turned out that most people had enhanced memory of where they were and what they were doing upon receiving the news.

Intense, long-term memories are also forged by fear and are reawakened, throughout life, by stress. Studies of mice at New York University are instructive. When exposed to a ringing bell followed by electric shock, mice remember and fear the sound of the bell, explains neuroscientist Joseph LeDoux. If, in subsequent trials, the bell rings, but the shock is withheld, the fear response and the memory that triggered it seem to fade. But once shocked, the mice are forever predisposed to fear. The terror returns with a vengeance if previously shocked mice are exposed to stress in other situations even if those mice have not been stressed for months.

A Sea Slug Remembers

The sea slug is an ideal model.

Hoping to unravel the molecular biology of this process, Kandel started to study learning and memory in mammals. But monkeys and even mice, with brains much like ours, were just too complex. Casting around for a simpler system to study, he hit upon Aplysia, the sea slug. This creature, he reasoned, would be ideal. Aplysia have relatively few nerve cells, some 20,000 in all, many significantly large in size. And a sea slug has a couple of simple, learned behaviors, including withdrawal of its gills or its tail in response to stimulation, that could be used to study memory over the short and long term.

As to the cellular site of memory storage, Kandel guessed it to be the synapse, the space between one neuron and the next. The reasoning was simple: whether in humans or sea slugs, mature neurons had long since lost their capacity to divide. Memory could not, therefore, result from proliferation of new neurons. It could, however, be etched into the neural network if existing nerve cells simply expanded, growing more branches to communicate with other nerve cells in more effective and powerful ways.

Working with sea slugs, Kandel soon proved that the synapse between cells was indeed the point at which learning and memory could be etched in stone. A single, brief pulse of stimulation to a sea slug, for instance, caused its gill to withdraw for minutes. That brief reflex was due, invariably, to release of the neurotransmitter serotonin from the stimulated neuron. The serotonin simply crossed the synapse and temporarily modified proteins in the membrane of the target cell leading to production of such messenger chemicals as cAMP (cyclic adenosine monophosphate) and protein kinase A.

In long-term memory, messengers activate transcription.

Five pulses of the same stimulation, meanwhile, led to a long-term response in which the sea slug's gill withdrew for weeks. Here, protein kinase A was produced in such abundance that it provoked production of another, similar molecule called mitogen-activated protein kinase, or MAPK. Together, these two molecules traveled to the nucleus of the cell and activated the gene transcription factor, CREB-1. Kandel found that CREB-1 works by binding to DNA in the nucleus of the cell and then switching on genes that result in automatic production of yet more protein kinase A, even when no further stimulation occurred. Long-term memory, reflected in the extended flexion of the tail and the neural architecture of the sea slug, was the result.

Remarkably, Kandel and others have found that brain regeneration may be thrust into hyperdrive by a phenomenon characteristic of neural cells only. Messenger RNA molecules normally must travel to carry instructions from DNA in the nucleus of a cell to the point of protein synthesis within its cell body, or cytoplasm. But in neurons, it seems, some messenger RNA molecules already reside at the synapse, where they can be turned on to make new proteins, in some instances without immediate instruction from nuclear DNA.

The implications are profound: if this system were switched on through pharmaceutical intervention, notes Unterbeck, it could enable an especially rapid rate of protein creation at the synapse and might even facilitate the "functional regeneration" of brain cells required to treat Alzheimer's disease, Parkinson's disease, Huntington's disease, and other illnesses notable for wholesale neuronal death.

Mammal Memory

Memory and learning are highly conserved.

On every level, the connections between memory and treatments are profound. "It turns out that the principal pathways involved in memory and learning are highly conserved throughout evolution, from sea slugs and flies to rodents and primates," Unterbeck explains. "The reason is that these skills are the key to survival for any animal species. To find food, to avoid danger, to navigate new environments, even to find a mate or reproduce, memory and learning are involved."

While it isn't possible to do real-world experiments with humans, the researchers have made enormous progress with genetically modified mice. Exposing these rodents to proteins discovered in Kandel's cascades, the Memory Pharmaceuticals scientists have been able to toggle the genes in nerve cell nuclei, switching them on and off. As a result, the mouse equivalent of long-term conscious memory, as measured by performance in a learning maze, has been diminished or improved. "Depending upon what we do," Unterbeck explains, "we can make the same animal perform brilliantly or with impairment." It all depends on the ability or inability of the brain to consolidate that memory to activate the genes that produce the proteins that lay the memories down.

Memory as Business Model: The Age of Cognostics

We finally know enough to intervene.

Sitting in his New Jersey office and reflecting on the implications, Unterbeck says the news is extraordinarily good. In 2001, we finally know enough about the process to intervene. "We have taken the science and translated it to a business plan," Unterbeck says, implying by tone, by expression, and by the very way he sips his Pellegrino that this new step excites him most.

"Drug discovery, in principle, happens at the interface of medicinal chemistry and biology," he explains. For memory drugs, the intersection is the synapse, where proteins create new patterns in the brain. "We are searching the molecular pathways of memory for single proteins that can be used, pharmacologically, to repair impairments at the level of the synapse," Unterbeck states. For Kandel, Unterbeck, and Memory Pharmaceuticals, the means to this end is functional genomics - tracking memory through the cascade of genes and molecules, all within the context of a particular impairment in a specific part of the brain.

Cognostics puts drug candidates through the paces - fast.

The industrial-scale discovery platform they hope will "crunch" the molecules goes by the name of Cognostics. Essentially a test track for the pharmaceutical future, Cognostics puts promising drug candidates through the paces in record time. The first level of the Cognostics platform includes cell-based assays - one for each biochemical pathway discovered by scientists like Kandel. This "high throughput system can test thousands of compounds a day," Unterbeck states.

Candidates passing muster in level one of the Cognostics platform are shunted on to level two: a series of physiological assays that test the pathways in tissue; in this case, slices of hippocampus from the brains of mice. Here, Memory Pharmaceuticals' scientists track the electrical stimulus required for "long term potentiation" of the memory system under a variety of circumstances, including those simulating human aging and memory-related disease. Semifinalists in this long-distance race for memory-enhancing compounds are, finally, passed on to level three of the Cognostics platform - tests in live animals, starting with mice.

The focus is on pathways upstream of the memory genes.

Although Unterbeck cannot reveal the leading contenders in this Darwinian competition between drug candidates, he notes the focus is on "pathways upstream of the genes," that is, proteins at work early in the cascade of events needed to turn the memory genes on. "You can go as far upstream as the cell surface," he says, where powerful neurotransmitters such as serotonin and dopamine come to mind. Memory Pharmaceuticals has not targeted these usual suspects, however, but other, novel enzymes and receptors still are unprotected by patent approvals and, thus, still are under lock and key.

Once the winning compounds have passed the Cognostics screening system, the first new drugs will start to emerge. Initial applications will be for memory loss stemming from dementia - Alzheimer's and Parkinson's - as well as cognitive deficits tied to schizophrenia, depression, and other forms of psychiatric disease. These products, moreover, could be coming soon. Unterbeck estimates his group is just 12 to 18 months from submitting an investigational new drug (IND) application to the Food and Drug Administration so that the multistage process of clinical trials can begin. Already interested in the chance to participate in these trials is the Neurology Group at Columbia University, where such world renowned Alzheimer's experts as Richard Mayeux will lead the charge.

The second generation may target senility and cognitive diseases.

Thereafter, says Unterbeck, a new generation of memory drugs might target those with age-related memory deficit stemming not from Alzheimer's, but rather garden-variety senility and cognitive diseases first noted in childhood - attention deficit disorder, autism, Down Syndrome, and epilepsy, to name a few.

The spectacular promise prompts a final question: will such intervention lead to memory and cognitive enhancement for people already in the normal or even superior realm? While that is not the goal of Memory Pharmaceuticals, it is clearly in the wings for society at large. Given the right biochemical jolt to their memory pathways, normal mice put through the paces at Memory's labs have actually been able to push the outside of the rodent envelope in maze experiments. It is, as Unterbeck states, "a mosaic." When we comprehend the pathways, we will be able to modulate them in untold ways. At the very least, we should be able to learn from experience recall our lives, good, bad, or otherwise, to the very end.

Pamela Weintraub is a science journalist based in Chappaqua, New York.
Cary Barnhard grew up in New Jersey, where his senior class voted him "most unique." He maintains that honor is a polite way of being voted "most likely to need therapy." After a few misadventures in the music industry, he started pretending to be a graphic artist. Eventually it became the truth.


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Endlinks

Three Share Nobel Prize in Medicine for Studies of the Brain - New York Times article from October, 10, 2000. Free registration required.

The Future of Psychiatry: Eric Kandel Says It Lies With Biology - an article about this scientist, with related links, from the September 2000 issue of HHMI Bulletin.

Controversy Surrounds Memory Mechanism - discusses the connection between long-term potentiation and memory. From the March 1, 1999 issue of The Scientist.

Alzheimer Research Forum - offers extensive resources for researchers, including an interview with Richard Mayeux.

Making Memories Stick: Cell-Adhesion Molecules in Synaptic Plasticity - considers the role of another class of molecules in memory formation. From Trends in Cell Biology, 2000, 10:11:473-482. Full text available from BioMedNet.

Involvement of Hippocampal Synaptic Plasticity in Age-Related Memory Decline - discusses experimental results in the context of theoretical models of synaptic plasticity. From Brain Research Reviews, 1999, 30:3:236-249. Full text available from BioMedNet.

Genetic Approaches to Memory Storage - a review by Mark Mayford and Eric R. Kandel. From Trends in Genetics, 1999, 15:11:463-470. Full text available from BioMedNet.

Molecular Mechanisms of Synaptic Plasticity and Memory - explores the link between synaptic plasticity and memory formation. From Current Opinion in Neurobiology, 1999, 9:209-213. Full text available from BioMedNet.

Sleep: Off-Line Memory Processing - a review of behavioral and physiological studies. From Trends in Cognitive Sciences, 1998, 2:12:484-492. Full text available from BioMedNet.

Positive and Negative Regulatory Mechanisms that Mediate Long-Term Memory Storage - a review by Ted Abel and Eric Kandel. From Brain Research Reviews, 1998, 26:2-3:360-378. Full text available from BioMedNet.

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