The snail and fly experiments showed that CREB, which hangs out near the nucleus of a brain cell, is a molecular "general contractor" for memory formation. CREB helps turn on the genes needed to produce new proteins that etch permanent connections between nerve cells; it is in these links that long-term memories are stored. The Tully and Kandel teams also found a second factor: CREB repressor. Yin and Tully engineered flies with excess CREB repressor, and they failed to form memories even after many tries. CREB repressor apparently stops the brain from bogging down in random details.
Viagra for the Brain
Robert LangrethBiotech firms are tantalizingly close to unraveling the mysteries of memory. On the way are drugs to help fading minds remember and let haunted ones forget. Inside a small lab in an anonymous office park off the Garden State Parkway in northern New Jersey, researchers probe the molecular intricacies of memory. Tiny metal electrodes zap minute jolts of electricity at precise intervals into slices of rat brain suspended in nutrient broth in plastic lab dishes. This simulates the electrochemical changes that occur in brain cells when a new memory is created. A robotic pump drips experimental drugs through plastic tubes onto the brain cells, while other electrodes measure how each drug alters their activity. Six such setups chart the mind-altering effects of dozens of compounds a month. Most have little effect, but a few drugs fit a cherished profile: helping the disembodied neurons form stronger, longer-lasting connections.
Memory Pharmaceuticals, the closely held biotech firm doing this work, is at the forefront of an intense scientific race to devise the first effective memory-enhancing drug. The idea has long been the stuff of science fiction, but now researchers are decoding the molecular details of how memories are formed and how they are lost. They have taken a crucial first step: identifying the genes and proteins inside brain cells that regulate memory formation. They are tantalizingly close to creating a kind of Viagra for the brain: a chemical that reinvigorates an organ that has faded with age. This new generation of drugs could mend memory loss in the seriously ill or the merely absentminded.
"My friends keep asking when the little red pill is coming," says Eric Kandel, 72, the elder statesman of the field, a Columbia University researcher who founded Memory Pharmaceuticals in 1998 and won the Nobel Prize in 2000. He began his work in the 1950s, when most researchers viewed it as futile. "If we continue making the kind of progress we are now, we will have drugs for age-related memory loss in five or ten years," he says.
At his lab chemists have concocted prototypes that counteract age-related memory loss, making grizzled mice race through mazes as quickly as younger ones. Human trials could begin next year.
Kandel's archrival in this race is 25 years younger and a bit more brazen: Timothy Tully, 47, a researcher at Cold Spring Harbor Laboratory and a founder of privately held Helicon Therapeutics in Farmingdale, N.Y. He hopes to begin human trials in two years.
Other small biotechs and big drug firms, including Merck, Johnson & Johnson and GlaxoSmithKline, also are in pursuit. The prize is a stake in what will be one of the next huge global drug markets.
The first users will be the four million Americans with Alzheimer's disease, but ultimately the market may be far larger. Several million people have so-called mild cognitive impairment, and Pfizer and J&J now are testing whether this can be treated by their already-approved Alzheimer's drugs, Aricept and Reminyl.
The market ratchets up quickly from there. Depending on their mechanism of action, memory drugs might work in the treatment of millions of people with head trauma, Down's syndrome or mental retardation. Patients recovering from severe strokes may one day ingest memory drugs while getting cognitive therapy to relearn basic motor skills and speech. Some new drugs may even block bad memories
The big score: treating 76 million middle-aged folks who aren't demented but may welcome a way to reverse the frustrating forgetfulness that comes with age. "People in the industry are thinking about it. It would be a huge market, but the drugs would have to be very safe," says Novartis research chief Paul Herrling. Adds James McGaugh, a neuroscientist at the University of California, Irvine: "Drug companies won't tell you this, but they are really gunning for the market of nonimpaired people--the 44-year-old salesman trying to remember the names of his customers."
But a pill popped by millions of healthy people looking for a mental edge could pose serious risks. Forgetfulness is an important part of proper mental function. A too-potent drug might wreak havoc on emotions or fill the brain with useless clutter. The pill would have to be free of side effects before it could be used for mild deficits. Regulators would balk at clearing a lifestyle drug that has any risk associated with it. The big question, of course, is whether these drugs will in fact do what is expected of them. Some scientists are skeptical about that.
But if Kandel and Tully succeed, they will forever alter medicine and how we view the world. Ever since 17th-century French philosopher René Descartes famously divided the world into two parts--"extended things" (the physical world) and "thinking things" (the mind)--philosophers and scientists have debated whether the human mind is so elusive as to be unknowable. A memory drug would knock out the few pillars still supporting the view that the mind exists apart from the gray, cellular mush of the brain. Says Tully: "Memory is a biological process that can be manipulated by modern biology like anything else. Not only can you disrupt it, you can improve it. Descartes was wrong."
Should a bottle of memory pills appear on your nightstand one day, a heap of credit will go to Tully and Kandel, with an assist from two of God's lowliest creatures: the fruit fly and the sea slug. Kandel, a forceful, Brooklyn-bred and Harvard-trained polymath, was born in Vienna in 1929 and fled to the U.S. with his parents in 1939, months before World War II began. The vivid memory of Nazi horrors, in part, drove him to study the mind. As a promising young psychiatrist, he gambled his career on a hunch that studying sea slugs could yield insights into human memory. In the decades since, his lab at Columbia University's Howard Hughes Medical Institute has dominated the field. But even after winning the Nobel, he still hasn't persuaded all his peers that his sea-slug studies explain human memory. An effective drug would vindicate a lifetime of scientific pursuit.
Tim Tully, a down-to-earth Irish Catholic with blue-collar roots in Peoria, Ill., studied genetics at the University of Illinois at Urbana-Champaign. His ten-person team of researchers at Cold Spring Harbor Laboratory has battled Kandel to a draw by producing, in a dramatic series of experiments, fruit flies with photographic memory.
At the heart of both men's research is a startling fact: The basic mechanics of memory formation in humans aren't much different from those of snails, flies and other simple creatures. Brain cells seem to be similar in all animals; the difference is in the complexity of the wiring that links them. "Humans are like laptop computers, and flies are like Philco radios," says Tully.
This wasn't at all obvious when Kandel got started in the late 1950s, when most scientists assumed the human brain was far more advanced. Early on, after graduating from Harvard with plans to become a psychoanalyst, he detoured into research after becoming fascinated with new methods for probing the electrical activity of brain neurons.
About this time, scientists got their first serious clue to how and where memories are formed. A 27-year-old patient, known in medical literature only as H.M., had severe epilepsy. In an attempt to cure it, surgeons in 1953 removed his hippocampus, a small ridge in the center of the brain. His seizures went away and his reasoning capacity was intact, but he could no longer recall any new facts for longer than a few seconds. Oddly, though, H.M. had no trouble remembering his childhood. That hinted the hippocampus was crucial for converting immediate perceptions into memories yet wasn't the storage site.
Inspired, Kandel focused on the cellular workings behind memory. He chose an animal that would be easy to study: the lowly sea slug, Aplysia. It has 20,000 central nervous system cells so big they can be seen without a microscope. (Humans have 100 billion brain cells.) Kandel turned down an offer to run the psychiatry department at Harvard's Beth Israel Hospital and bet his career on the slugs.
In a series of landmark studies, Kandel began to show how simple memories are formed by gauging one of the slug's basic reflexes: the withdrawal of its gill at a perceived threat. He learned that a slug's nerve cells (and, by implication, human brain cells), perform a subtle electrochemical mating dance that reinforces links between them. A short-term memory is like a one-night stand, held together by fleeting but intense surges in chemicals that bind cells together. The effect fades away minutes or hours later. Long-term memories are more like marriages, cemented in place for weeks or years with new proteins that reinforce the synapses connecting the cells. Even these, however, erode with time. By the mid-1970s Kandel was a star. Though prone to brutal candor in describing the work of lesser scientists, he mesmerized colleagues with sweeping lectures, encyclopedic knowledge and charming wit. "He is just about the smartest guy I know," says Johns Hopkins neuroscientist Solomon Snyder.
The advent of biotech in the late 1970s allowed Kandel and others to explore memory on a molecular level. That was crucial: Once the molecular workings are understood, drug targets become easier to find.
Kandel helped show that a messenger called cyclic-AMP (adenosine monophosphate) played a central role in memory formation. It sits inside the surface of a cell and springs into action when signaled by other cells, activating proteins that temporarily boost the connection between two nerve cells. But cyclic-AMP is just a messenger; it doesn't churn out the new proteins essential for building long-term memories. In 1990 Kandel found an intriguing molecule, CREB (c-AMP response element binding protein), that appeared to be involved. His team showed that blocking CREB in sea slug nerve cells also blocked new long-term memory, without affecting short-term memory.
Kandel had the first clues, but the most dramatic proof in understanding just how much CREB influences memory came from Tim Tully and his Cold Spring colleague Jerry Yin. Tully's fruit flies had advantages over sea slugs: a wider range of behavior, easy genetic engineering and an ability to be bred by the millions in test tubes. In 1994 Tully and Yin created fruit flies with photographic memories by engineering them with the CREB protein switched into the "on" position. Normal flies took ten tries to learn to avoid a scented chamber where they would get an electric shock. Tully's superflies learned after just one try. Since then, other researchers have shown CREB plays a similar role in mice.
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Who's Who in the Race for RecallCortex Pharmaceuticals
How it works: Acts as hearing aid for aging neurons, magnifying signals from other brain cells .
When: Human trials under way.
How it works: Blocks a serotonin receptor that is prevalent in the hippocampus.
When: Human trials in Alzheimer's patients starting.
Johnson & Johnson
New Brunswick, N.J.
How it works: Blocks histamine-3 receptor, which may be involved in alertness, attention and memory.
When: Entering human trials for jet lag or memory loss.
Drug: Phosphodiesterase-4 inhibitors; other approaches
How it works: Indirectly boosts memory by preventing the breakdown of cyclic-AMP, a key cellular messenger.
When: Human trials in 12 to 18 months.
Drug: PDE-4 inhibitors and others
How it works: Indirectly boosts CREB memory protein.
When: Human trials within two years.
Merck & Co.
Whitehouse Station, N.J.
Drug: GABA inverse agonists
How it works: Modulates GABA receptors to increase alertness in brain regions central to learning and memory.
When: In lab testing; plans for human tests undisclosed.
New York, N.Y.
How it works: Activates various memory genes.
When: Human tests 12 to 18 months away.
Pfizer/Natl. Inst. on Aging
New York, N.Y.
What and when: NIA now testing whether Pfizer's Alzheimer's drug Aricept can protect people with mild memory loss from Alzheimer's.
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The superfly results were so astonishing that Tully kept them secret while he prepared to publish them. But Kandel got an early peek at Tully's work, because at the time he was on a panel reviewing Tully's grant application. Tully contends Kandel conducted similar tests on sea slugs and tried to pass off his results as a first. This sparked a spat, and Tully retaliated a few years later by taking a jab at Kandel in an article he wrote for a prominent medical journal. Asked about the rift, Kandel dismisses it as a distraction from the science and says of his younger rival: "Tully is very good. He is a worthy competitor."
Cyclic-AMP and CREB are now targets for drugs. In 1998 Kandel's team injected aging mice with a failed antidepressant called Rolipram, which prevents the breakdown of cyclic-AMP by blocking an enzyme called phosphodiesterase-4. The hope was the drug would boost old, tiring brain cells. Rolipram, though developed in the late 1980s, never made it because it did not work well and caused nausea and vomiting. But, sure enough, old mice on Rolipram began navigating mazes faster.
Kandel shared the amazing results with his friend, Walter Gilbert, a Nobel laureate at Harvard who founded Biogen. Gilbert contacted venture capitalist Jonathan Fleming of Oxford Bioscience Partners, who helped raise $38 million to form Memory Pharmaceuticals. Axel Unterbeck, then head of dementia research at Bayer, signed on as president. "I was stunned. Never had I seen data like this," says Unterbeck, now Memory's chief science officer.
Now Kandel is devising a Rolipram-like drug that targets the brain's memory centers but avoids regions that control the vomiting reflex. It turns out some 20 variants of phosphodiesterase-4 play different roles. Memory Pharmaceuticals researchers carefully mapped the regions in the brain where each variant is found. It is testing prototype drugs that block those present only in the hippocampus. In animal tests, the compounds duplicate Rolipram's success without the nasty side effects. The first human trials are about 18 months away, most likely first in Alzheimer's. Says Unterbeck, "If it is safe, the market is incalculable."
Tully's Helicon Therapeutics is keeping pace. Under the direction of veteran biotech executive John Tallman, Helicon has screened 200,000 compounds for ones that boost CREB and cyclic-AMP, producing several drug candidates. So far Helicon's compounds have enabled mice to learn events associated with mild electric shocks twice as fast as normal. A legal showdown between Helicon and Memory may be in the cards. Helicon chief John Tallman says its CREB patent may prevent other companies from marketing memory drugs that target CREB pathways.
Numerous other brain molecules are involved in memory, and some may offer even better drug targets than CREB and cyclic-AMP. Cortex Pharmaceuticals in Irvine, Calif. has designed molecules, called ampakines, that amplify incoming signals from other neurons by targeting so-called AMPA receptors on brain cells. With a partner, it is beginning a second-stage trial with 160 patients with mild cognitive impairment. Another firm, Axonyx in New York City, hopes to begin human trials next year of a drug derived from the saliva of the gila monster.
Tully and Kandel also are looking for additional genes and proteins beyond CREB. Both are using DNA chips to scan thousands of genes at once. Success, says Tim Tully, is only a matter of time: "It's not an 'if'--it's a 'when.'"
SMART DRUGS 2: REVIEW