Medicine may allow us to challenge our genetic inheritance and repair insults to the brain, whether as Alzheimer's sufferers or moody, forgetful people and hazy thinkers.
Daryl Kipke is showing off his company's latest prototype, a state-of-the-art electronic chip. It's not the sort likely to end up powering your iPod, but it does produce a beat you won't be able to get out of your head—because this device is designed to be surgically implanted deep in your brain, where the chip will deliver electric signals to specific clusters of cells. Kipke's firm, NeuroNexus Technologies in Ann Arbor, Michigan, is developing and testing the device to deliver electric pulses that can relieve some of the symptoms of Parkinson's disease, obsessive-compulsive disorder, and depression. "Deep-brain stimulation has been poorly understood," says Kipke, who is also a University of Michigan neuroscientist. "But with this technology we can improve neuron targeting and tuning."
Kipke's device is only one of many new treatments in the pipeline for major brain disorders, treatments guided in some cases by the explosion in genetic data in the past decade. These illnesses already cost the U.S. alone more than $1 trillion a year in health-care bills and lost income, and that figure is almost certain to skyrocket with an aging population. As a result, money has been pouring into brain research—$5 billion in 2008 from the U.S. National Institutes of Health alone, plus hundreds of millions more from big pharmaceutical companies, major foundations, and even the Department of Defense, which wants to offer better treatments to veterans who suffer brain trauma. The result is an array of new approaches to boosting mental acuity and memory and restoring emotional balance in the afflicted.
But history makes clear that when re-searchers come up with a new treatment that makes us feel or work better, it's usually not just the truly sick who end up going in for an upgrade. The market for Viagra has gone far beyond those with medically documented cases of erectile dysfunction, for example. Casey Lynch, managing director of the neuropharmaceuticals market-strategy firm NeuroInsights, notes that much the same has happened with antidepressants. Before the current generation of these pills came out in the late 1980s, depression was estimated to afflict one out of 20,000 people, but today the figure is considered to be about one in 10 (due to more frequent and quicker diagnoses). The progress in developing treatments for illnesses that ravage memory and thought raises an important question: might the same tools be used to improve the functioning of minds that by most standards are already running fairly smoothly? We may well be approaching an era of designer brains, in which those of us feeling a little foggy or dull can have our IQ, fast recall, and self-confidence ratcheted up via the prescription pad or scalpel. "Some brain-related conditions we think of as ordinary," says Lynch, "may eventually become disorders, too"—including perhaps less-than-razor-sharp thinking.
The notion of a prescription IQ lift is hardly new. According to polls, about one in 20 college students, and higher percentages of professors, already illicitly pop some form of Ritalin or modafinil—legitimately prescribed for attention-deficit disorder and narcolepsy, respectively—to augment alertness, concentration, and memory. But these drugs have proved only mildly effective on normal minds, and carry potentially severe side effects ranging from addiction to overstimulation. Estrogen and testosterone supplements have also been only vaguely associated with improved cognitive functioning, and more strongly with serious potential risks. Meanwhile, about 4 million Alzheimer's sufferers worldwide take the drug donepezil, known as Aricept, to slow their mental decline, but most don't seem to benefit much.
Scientists had originally hoped that the decoding of the human genome would lead quickly to small groups of genes that control major mental disorders and traits, be they Alzheimer's disease, intelligence, or personality. That hasn't been the case; individual genes turn out in most cases to only weakly affect the brain, with most illnesses emerging from the interaction of large, complex networks of hundreds of genes. That challenge hasn't kept researchers from tracking down many of the genes in these networks to chip away at the genetic roots of mental disorders—and to come up with possible treatments based on some of those findings.
The result is that medicine may allow us to challenge our genetic inheritance and repair environmental insults to the brain, whether as Alzheimer's sufferers or just moody, forgetful people and hazy thinkers. Techniques undergoing testing now include altering genes within brain cells, or even pushing genes into creating altogether new brain cells. Neuro-logix in Fort Lee, New Jersey, for example, is developing brain-related gene therapies, which involve injecting harmless viruses that insert custom-built genes into cells. Though other experimental gene therapies have in the past often caused severe and even fatal side effects, Neurologix hopes to avoid them by targeting the viruses only at those cells that need repairing. The firm has a treatment for Parkinson's disease in clinical testing now, with versions for Huntington's, epilepsy, and depression in the wings.
Companies looking to spur the growth of new brain cells—a feat that until recently most scientists believed was impossible—include Seattle-based Sound Pharmaceuticals, which has restored hearing in mice by blocking a protein that keeps cells from growing, so that the mice grow new auditory sensory cells. "We've seen some neuronal generation, too," says Sound CEO Jonathan Kil. Other firms are promoting neuron regeneration to boost cognition and combat senility, while others are working to restore the white-matter cells that are savaged by Alzhei-mer's and other diseases. Stem cells—sort of generic proto-cells that can be coaxed into maturing into any specific type of cell—have also been employed to replace damaged neurons, with some encouraging results. Anders Haegerstrand, chief scientific officer of Stockholm-based Neuro-Nova, predicts his company will have a stem-cell-based Parkinson's treatment on the market by 2013. "I wouldn't dare speak of a human cure for the disease," he says, "but we've cured it in many monkeys."
We won't necessarily have to turn to these more radical therapies to sharpen our thinking. The genetic and other new scientific insights into the brain are also helping to point the way to new drugs targeted at brain disorders—drugs that may also end up being taken as smart drugs by many of us without serious disorders. About one in five clinical drug trials currently underway address brain-related illnesses, including some 300 drugs for Alzheimer's alone—and at least 40 of these candidate drugs have the potential to end up as IQ- or memory-boosting drugs. Among the many small companies that have sprung up to focus on such brain-tuners are CoMentis, a South San Francisco firm trying to develop a drug that offers the mind-sharpening effects of nicotine without its addictive and other unhealthy aspects; San Diego–based Helicon Therapeutics, which is working with a protein that links short- and long-term memories; and San Diego–based Ceregene, which is looking at injectable viruses that activate invigorating "nerve growth factors" in brain cells. Accera in Broomfield, Colorado, already markets an FDA-approved, prescription-only "medical food" designed to get extra energy to brain cells, and it has been shown in studies to slight-ly boost cognitive test scores for some Alzheimer's sufferers and others. "The scores start improving within 30 minutes of drinking it," boasts Accera CEO Steve Orndorff.
The lineup of drugs is likely to lengthen rapidly in the coming years as new discoveries spill out of the lab. In just the past year researchers have found that a protein known as "death receptor 6," which plays a role in the normal development and selective "pruning" of brain and other cells, also appears to wreak wholesale havoc in the brains of those suffering from Alzheimer's and other disorders, causing brain cells to essentially commit suicide. Chemicals that block DR6 have already shown promise in the lab as a way of preserving cognition and memory by interrupting the chemical signals that appear to trigger the mass suicides. The biotech company Genentech in South San Francisco has already achieved some success with DR6 blockers in slowing brain disease in mice, and may be ready to start human trials next year. In theory, such blockers might also eventually prove useful in slowing memory loss and confusion even in normal aging brains. Other research has turned up molecules in the brain that appear to be critical for forming memories, and studies have shown that injecting these chemicals into brains can improve memory in mice. Labs have even demonstrated drugs that block memories, a technique that could in theory restore and sharpen minds by helping to selectively erase traumatic and distracting thoughts—an idea that seemed farfetched when fictionally showcased in the 2004 movie Eternal Sunshine of the Spotless Mind. "It would be great to have this sort of drug in the toolbox for working with traumatic memories that don't respond to other techniques," says Naomi Mael Litrownik, a Needham, Massachusetts, therapist who works with traumatized patients.
Some of the most striking results in altering brain function have come not from genomic science as much as from advanced imaging techniques, which give scientists a view of how the brain functions. Until about five years ago, scientists were sure higher intelligence was mostly seated in the front section of the outer layer of the brain, but now it's clear that the sides and back of this "gray matter" contribute as well—in fact, the more gray matter a person has anywhere in the skull, the higher his or her IQ is likely to be, as a rough rule. The amount and quality of the "white matter" underneath, which harbors the physical connections between brain cells, are linked to intelligence as well. Knowing this brain structure in detail has allowed scientists to experiment with applying electric signals directly to various parts of the brain via implanted wires and devices. Neuro-Nexus, for in-stance, hopes to improve its spinal-cord chip therapy by enabling doctors to adjust, via trial and error, which of thousands of nodes on the chip are activated, fine-tuning patient response as different brain cells get juiced. Such deep-brain stimulation has not only been shown to smooth tremors and fend off seizures, but has also in many cases been associated with cognitive and personality changes, holding out the possibility that mental acuity and mood could someday be fine-tuned as well. It may not even require brain surgery, notes Will Rosellini, CEO of MicroTransponder, a Dallas startup that's on the way to bringing to market a device that stimulates the vagus nerve in the neck. "It's a way of reprogramming the cortex from outside the brain, and some of the results are very exciting," he says.
Many of these experimental drugs and treatments are likely to wash out due to side effects, and even if they don't, government regulators aren't likely to approve their use for anyone who doesn't suffer from a serious disorder. Some researchers are hoping to develop more natural methods that could have the same IQ-boosting effect in healthy people as drugs and other treatments. The adult brain has turned out to have a surprising ability to extensively reconfigure its connections through mental exercises. Most of us have parts of our brains that are relatively neglected, says Daniel Siegel, an associate clinical professor of psychiatry at UCLA Medical School, and we can restore them by techniques such as focusing on nonverbal cues when we're conversing with other people, being more aware of what we're thinking, and easing up on the multitasking. "When you do several things at once you tend to do them on autopilot, and fail to engage the parts of the brain that form strong neural connections," explains Siegel. For many people, however, the temptation of neuroenhancers may be hard to resist. The ethical dilemma it poses is a side effect of our new knowledge of the cell.