Can I Grow A New Brain?

By Paul Hoffman

Long before neuroscientists took the first tentative steps toward brain-tissue transplants (let alone dared to think about whole-brain transplants), mischievous philosophers were plumbing the consequences of such 21st century surgery. "In a brain-transplant operation, is it better to be the donor or the recipient?" these wags asked. To put it another way, if you and Tom manage to swap brains, who is now the real you? The man with your brain attached to Tom's body or the man with Tom's brain joined to your body?

The real you, it can be argued, is the man with Tom's body; he's the one who knows the most intimate and embarrassing details of your life. The man with your former body may now have a bum knee, but he won't know why (that misguided dive you took playing touch football to impress your girlfriend in 1971). Summing up his own theoretical musings about the wisdom of a brain swap, Tufts University philosopher Daniel Dennett concluded that it was not an even exchange. "It was clear that my current body and I could part company, but not likely that I could be separated from my brain," he wrote. "The rule of thumb [is] that in a brain-transplant operation, one want[s] to be the donor, not the recipient."

Whole-brain transplants are still science fiction. "I never like to say that something's impossible," says Dr. Evan Snyder, a neuroscientist at Harvard Medical School and Children's Hospital in Boston. "I've been burned too many times by categorically ruling something out. And yet I can't imagine that 20 years from now human-brain transplants will be possible. The connections required are just too complex; they number in the millions. But the future of brain-cell transplants--that's another matter."

So far, medical science has had only mixed results with brain-cell transplants. Take the treatment of Parkinson's disease, for example, a condition that is gradually depriving more than 1 million Americans of their ability to move and speak. The disease is caused by the slow deterioration of brain cells that produce dopamine, a chemical essential for the transmission of messages from the brain to the rest of the body. A decade ago, Swedish researchers started implanting dopamine-producing cells from human fetuses into the brains of Parkinson's patients. The treatment improved the mobility of many of the patients but usually only partly and in some cases not at all. Even if the treatment becomes more successful (and the ethically charged issue of mining aborted fetuses is overcome), it can hardly become routine. For each patient, cells from as many as 15 fetuses must be harvested and transplanted almost immediately.

Yet as the Decade of the Brain proclaimed by President George Bush draws to a close, neuroscientists are increasingly sanguine that in George Jr.'s lifetime, brain-cell transplants may reverse, if not cure, a host of neurological diseases such as Parkinson's and Alzheimer's, as well as brain damage caused by strokes and head injuries. Even a year ago, such a sweeping claim might have been dismissed as nonsense. But that was before last fall's discovery that the fetal human brain contains master cells (called neural stem cells) that can grow into any kind of brain cell. Snyder extracted these cells and "mass-produced" them in the lab. His hope is that the cells, when injected into a damaged adult brain, will turn themselves into replacements for cells that are dead or diseased.

When most physicians got their training, they were taught that the adult brain is rigid, that its nerve cells, or neurons, could never regenerate themselves. If you nick your finger with a knife, the cut will heal in a few days because your skin has the ability to generate new cells. But when something bad happens to the brain, it doesn't repair itself. Why's that? "The brain is not plastic," says Snyder. "It doesn't make new cells. You are born with more brain cells than you need, and you lose them progressively and get dumber and dumber as you get older--or so went the conventional wisdom."

The path to overturning the dogma of the rigid brain was circuitous. In the early 1960s biologists discovered that new cells were being made in two areas of the adult rat brain, but the discovery was regarded as an unimportant peculiarity of the rodent brain and quickly forgotten. In the mid-1980s, Fernando Nottebohm of Rockefeller University brought new respect to the term birdbrain by demonstrating that the brain of an adult canary has the astonishing ability to regenerate new nerve cells at a rate of up to 20,000 a day. Other researchers reported similar regenerative ability in fish and reptiles, but there was still no evidence that evolution had passed on this ability to the human brain. Indeed, most neuroscientists wouldn't even entertain the possibility of new cell growth in the human brain on the grounds that any additional cells would disrupt the brain's complex wiring.

Snyder was not so sure. "I'm an optimist. Why would evolution have been parsimonious in depriving the human brain of the power of self-healing? I was a pediatrician before I became a neuroscientist. As a pediatrician, I was impressed by how much plasticity there really must be in the human brain. Pediatricians know that damage to the infant brain doesn't have the same outcome as damage to the adult brain. If a newborn has a stroke, even in the cortex [an area important to higher intellectual functions], he or she may sustain it and develop quite normally. The exact same injury would put an adult in a wheelchair. I wondered if the source of the brain's apparent plasticity was at the level of the single cell."

Different kinds of blood cells, red and white, come from a single kind of stem cell in bone marrow. These chameleon-like stem cells transform themselves into whatever kind of blood cells the body needs. The skin and liver have their own stem cells. "Maybe there is a brain stem cell, a mother cell that gives rise to all types of brain cell," Snyder says he wondered. "I wanted to find this cell and harness it to repair injured brains."

In 1992 Snyder announced in print that his lab had removed stemlike cells from mouse brains and had grown them in a culture. Snyder then teamed up with Dr. Jeff Macklis, a colleague at Harvard Medical School who had engineered a strain of mouse whose neurons died off in a tiny region of the cortex where cells were not known to regenerate. Snyder injected the stem cells into the mice. Like heat-seeking missiles, the cells rapidly sought out the injured part of the cortex and transformed themselves into healthy neurons. "That's the beauty of stem cells," says Snyder. "You don't have to find the injury--the stem cells do it for you. They instinctively home in on the damage even from great distances." In another experiment, Snyder used stem cells to cure mice of a disease that resembled multiple sclerosis. And in his latest, unpublished work, Snyder introduced massive brain injuries in mice--including strokes to the cortex--and cured them with stem cells.

"Where was this all leading?" Snyder says he asked himself many times. "In 20 years would I have done nothing more than create a thriving colony of healthy, smart mice that are free of brain disease? You can't take it for granted that every medical advance in mice will also benefit people." But the evidence started mounting. Over the past three years, researchers have discovered that brain cells regenerate in primate-like tree shrews, marmoset monkeys and rhesus monkeys, all of which are closer to us on the evolutionary scale than are mice (except in Kansas). The real payoff came late last year, when Fred Gage at the Salk Institute and his colleagues in Sweden reported that nerve cells are regenerated in the human hippocampus (a portion of the brain related to memory and learning).

Gage's finding--coupled with Snyder's report that same month of stem cells in the fetal human brain--has stood neuroscience on its head, so to speak. As has the latest finding, announced last month by researchers at Princeton, that adult macaque monkeys are constantly growing new cells in the highest and most complex area of the brain, the cerebral cortex. Snyder is now flush with confidence that neuroscience will ultimately cure many, if not all, diseases of the human brain. "By the year 2020 I hope we will have an active way of treating damaged brains. If we can further understand brain-cell regeneration and harness the process intelligently, then re-creating the brain, or at least parts of the brain, may lie within our grasp. Obviously there are lots of hurdles to overcome. But if we can capture and bottle the brain's now recognized plasticity, we can cure all sorts of things, maybe even damaged psyches."

The idea of implanting brain stem cells, while not as dramatic as swapping whole brains, also raises intriguing philosophical questions. "Sometimes at seminars when I talk about my work," says Snyder, "somebody will ask me whether the introduction of these stem cells will alter memory." Do the newly generated cells distort or erase old memories? Or will the transplanted stem cells bring with them memories of their upbringing in a Petri dish?

"All this is meta-neuroscience," says Snyder, laughing. "But I tend to think that the cells will take their cue from the host that houses them" rather than remembering their past lives like so many cellular Shirley MacLaines. So, in the case of brain-cell implants, it would seem, it is better to be the recipient than the donor.

PAUL HOFFMAN is president of Encyclopaedia Britannica and author, most recently, of The Man Who Loved Only Numbers