The Brain An Owners Manual We baby-boomers have no intention of aging gracefully. Egged on by the multibillion-dollar pharmaceutical industry, we wrestle with the loss of hair, bone density, muscle mass, sexual vigor, and the ability to fit into last year's pants. But there is one loss for which there's as yet no pill to pop nor laser surgery to undergo--losing the sharpness of our minds. That prospect is so scary we don't even like to think about it. Fortunately, talented researchers are using their brainpower to discover ways to preserve yours--to reverse the effects of injury and disease and to head off memory loss. Meet five scientists whose work touches every wrinkle of that mysterious supercomputer between your ears.
By Ted Spiker

(FORTUNE Magazine) – MEMORY LOSS Michela Gallagher, Ph.D. Chair, Johns Hopkins University Department of Psychological and Brain Sciences

You can't recall a word that's on the tip of your tongue. When asked what you did last weekend, you blank. You worry that those are signs that you've partied too hard and fried too many neurons. Not so, says Michela Gallagher.

Chances are what's happening to you is something called age-related cognitive decline--a benign condition that slows the brain's ability to form new memories. Gallagher, 56, spent nearly a decade patiently studying the condition in aging rats, whose memories deteriorate in ways similar to those of humans. She helped show conclusively that age-related cognitive problems are not caused by a loss of brain cells. Rather, by comparing the gray matter of old rats that could remember well and old rats that could not, Gallagher was able to demonstrate that the two groups had different patterns of gene expression, involving about 100 genes associated with the hippocampus, the main staging ground for memories as they form (see diagram). Because humans have analogous genes, that knowledge is power: It can speed the development of memory drugs. Says Gallagher: "The tools are in hand to try to make the translation from animal models to therapeutics in humans." Gallagher is working with Saegis Pharmaceuticals, a biotech startup in Half Moon Bay, Calif., that is conducting clinical trials on three drugs that target brain functions associated with some of the genes.

In the pharma world, memory is one hot topic. Saegis is only one of at least 60 companies that are racing to develop and test a memory pill, which could be on the market within the next few years. The first such drugs are likely to be aimed at mild cognitive impairment, a serious deterioration thought to be a prelude to Alzheimer's, and Alzheimer's itself. Should such drugs prove effective, they might also significantly improve life for many of the 16 million Americans age 65 or older. "You could restore good cognitive function for people well into their 70s, 80s, and 90s," Gallagher says. Similar treatments for people in their 30s and 40s may stop, prevent, or delay age-related memory loss.

NEURODEGENERATIVE DISEASES Bruce Miller, MD Clinical director, Memory and Aging Center, University of California at San Francisco

In the mid-1990s a patient with a paintbrush led neurologist Bruce Miller to discover a link between creativity and dementia. The patient, a man in his late 50s, was one of 350,000 Americans with frontotemporal dementia, or FTD, which kills cells in the brain's frontal and temporal lobes, between the left ear and eye, and robs a person of language skills, social graces, and emotional control.

Miller assumed that as his patient's dementia worsened, his artistic skills would also have deteriorated. "Oh, no," the man's son said, "they've gotten much better." The son sent samples of his father's artwork over the previous ten years, and what Miller saw amazed him: a progression from abstract paintings, filled with squiggles and colorful lines, to representational pictures with vivid detail--a purple bird the man remembered from a visit to Hawaii and an elaborate sailboat scene (which now hangs in Miller's office). "He started off with little talent and developed ability," says Miller. "At the same time, he became very eccentric, wearing only purple shirts and yellow pants every time I saw him. You see purple and yellow all over his paintings."

The patient's development led to further studies on how the brain can gain strength in some areas even as it fails in others. Miller began to encourage dementia patients to focus their rehabilitation efforts accordingly--emphasizing areas in which their minds still function well.

Miller, 54, whose clinic sees about 600 patients a year for Alzheimer's and other neurodegenerative disorders, watches his subjects carefully for clues about brain structure. "Good research begins with a single observation," he says. Miller recalls the case of a man whose first sign of dementia was loss of empathy. The man's wife accidentally snipped off the tip of a finger while gardening. Before helping her, he strolled over to the neighbors' to give them the pruning shears, saying that he wasn't going to need them anymore. He then told his wife to get inside so her geysering finger wouldn't cause a fuss, thus embarrassing him. And he claimed he couldn't drive her to the hospital until he found his driver's license, in case he got pulled over by police. This one man's strange behavior led to a series of studies that eventually revealed how patients with dementia lose function of their amygdala--the part of the brain that controls emotion.

There is currently no cure for dementia. But Miller hopes that a more thorough understanding of how odd behaviors signal changes in the brain will lead to the development of early-intervention drug therapies. Then, he says, "we could treat the disease before too much of the brain is damaged."

TUMORS Keith Black, MD Director of Neurosurgery, Cedars Sinai Medical Center, Los Angeles

Your brain has a doorman. It's called the blood-brain barrier--a network of special capillaries embedded within the organ to protect it from toxins and bacteria that could wreak havoc if allowed through, causing everything from seizures to comas. This doorman, however, can also block potentially helpful substances--such as medicine--from getting past the velvet rope. That's a major problem for people with brain cancer.

"It's been estimated that 98% of drugs for brain tumors cannot reach the brain effectively," says Keith Black. In his research Black discovered a molecular difference between capillaries in tumors and capillaries in healthy parts of the brain. He was able to develop a drug-delivery system based on this discovery that opens the door, enabling potent chemotherapy drugs to pass through the blood-brain barrier and attach specifically to the tumor without destroying healthy tissue. "That's the best of both worlds." says Black. "The drugs can get to the diseased part of the brain without being toxic to the normal part." Early studies of Black's treatment on human tumor cells in lab tests showed a threefold to tenfold increase in the effectiveness of drug delivery. Human clinical trials are expected to start within a year.

Black, who performs about 200 major brain operations every year, is also developing a vaccine that strengthens the body's immune response to brain tumors. The incidence of brain cancer has increased 25% since 1973, in part because of improved detection of tumors but perhaps, Black hypothesizes, also as a result of environmental toxins. "We know," he says, "that in lab animals, a number of toxins that are in our environment will cause brain tumors, from ultrafine particles of highway pollution to nitrites in hot dogs."

His vaccine is composed of specialized "antigen presenting" white blood cells that are extracted, treated with proteins from tumors, and injected under the patient's skin. They activate killer T-cells in the immune system, which then seek and attack the tumors. In one study, 39% of vaccine-test subjects had a survival rate of more than two years, vs. only 8% in the control group. Compared with the relatively crude ways we fight cancer now--burning tissue with radiation, cutting out tumors--Black sees such specialized, pinpoint therapies as the future. "As we begin to make these kinds of breakthroughs and understand the biology and physiology, we're able to design more intelligent therapies," he says.

DIAGNOSTICS Ron Hayes, MD Director, Center for Traumatic Brain Studies, McKnight Brain Institute, University of Florida

It's hardly a news flash that bonking your head, hard, can damage your brain. But that initial whack may not be the cause of your concussion or more severe trauma. When you're injured, your brain releases enzymes called proteases that can do further damage--well after the injury. "Think of the proteases as little Pac-Men that are asleep," says Ron Hayes. "After an injury, they become activated and start scooting around, chewing up everything in sight. Your brain tissue will continue to shrink for months after an injury. The brain ends up digesting itself."

The problem right now, Hayes says, is that doctors have no way to locate or monitor the release of the proteases. Post-whack, today's imaging tests--MRIs and CT scans--show only the physical characteristics of an injury, like swelling. There are blood tests that can discern diabetes or high cholesterol, but none exist to show chemical changes in the brain after a trauma. "We're completely blind," Hayes says.

Last year Hayes, 59, started a biotech company called Daimonion Diagnostics to develop the missing tests. He plans to have a prototype within three years. Hayes's ultimate goals are even more ambitious: to create high-tech scans that can map both the physical and biochemical structure of the brain.

If Hayes (or someone else) succeeds, doctors and paramedics in the future may have portable kits that instantaneously gauge an injury's severity. Then, by monitoring the chemical makeup of the brain at each stage of treatment, doctors will be able to conclusively determine the most effective drugs for each patient. Such tools could also be used to diagnose risk factors for diseases like Alzheimer's or Parkinson's. (One theory is that such conditions can be set off by trauma that damages the blood-brain barrier and allows destructive proteins to enter the brain.) They'd have preventive use as well, monitoring early signs of neurodegeneration and theoretically enabling doctors to prescribe drugs to prevent the onset of disease.

The fact that no such medicines are yet available doesn't daunt Hayes. If you build the tests, the drugs will follow, he predicts. "Where we are in the brain field is not in therapies, it's in diagnostics. There are drugs in the pipeline that we could use, but we don't have any way to assess how well they work. This will be the revolution."

MIND-BODY RELATIONSHIP Herbert Benson, MD Associate Professor of Medicine, Mind/Body Medical Institute, Harvard Medical School

In the 1960s Herbert Benson was laughed at more than Lenny Bruce. Curious about how stress related to heart disease, Benson, a cardiologist by training, began studying how the brain can affect the body. In his early research he discovered that people who meditated managed to decrease their blood pressure, rate of breathing, and metabolism (which reduces stress when it's slowed in the short term--for, say, ten minutes).

At a time when mind-body connections were considered kooky and were not even remotely the province of medical doctors, Benson wanted to learn more. He began to experiment with something he called a relaxation response--a two-step process. Step one was to repeat a word, phrase, or motion. Step two was to tune out all other thoughts. The idea was to harness the brain's power and use it in service of physical well-being.

Though the relaxation response was "reasonably ridiculed" at first, it turned out that it described a function of the hypothalamus, which controls the body's "fight or flight" response. Benson is now considered a pioneer in the flourishing field of mind-body medicine.

"More than half of doctor's-office visits are in the mind-body-stress realm, which is poorly treated by drugs and surgery," says Benson, 68. He sees medicine as a three-legged stool--surgery, drugs, and self-care--in which self-care encompasses nutrition, exercise, and the role of spirituality. While his studies have proved the relaxation response can treat the physical symptoms of anxiety, mild depression, hypertension, chronic pain, and insomnia, Benson says it's equally important for brain health: "When people are anxious, they don't remember as well. The relaxation response allows people to get over the stress and perform better and more efficiently."