DSRF Note:
Progressive damage to the brain is part of the syndrome for those who have Down syndrome. Prevention of that damage is part of our research program, which is based on an antioxidant therapy. That therapy cannot regenerate cells that are dead and it cannot restore lost mental capacity. But this new technology described as 'New Nerve Cells for the Adult Brain" has that potential.

There is a lot of research required and parents who want to support this research should contact the DSRF but be prepared to raise some money for research. We can't do anything unless you are willing to do your part.

All the work is done by just a few parents, so you can make a big difference.

"Reproduced with permission. Copyright © 1999
by Scientific American, Inc. All rights reserved."

Scientific American web page is http:/www.sciam.com

New Nerve Cells
for the Adult Brain

Contrary to dogma, the human brain does produce new nerve cells in adulthood.

Can our newfound capacity lead to better treatments for neurological diseases?

By Gerd Kempermann and Fred H. Gage

Cut your skin, and the wound closes within days. Break a leg, and the fracture will usually mend if the bone is set correctly. Indeed, almost all human tissues can repair themselves to some extent throughout life. Remarkable "stem" cells account for much of this activity. These versatile cells resemble those of a developing embryo in their ability to multiply almost endlessly and to generate not only carbon copies of themselves but also many different kinds of cells. The versions in bone marrow offer a dramatic example. They can give rise to all the cells in the blood: red ones, platelets and a panoply of white types. Other stem cells yield the various constituents of the skin, the liver or the intestinal lining.

The brain of the adult human can sometimes compensate for damage quite well, by making new connections among surviving nerve cells (neurons). But it cannot repair itself, because it lacks the stem cells that would allow for neuronal regeneration. That, anyway, is what most neurobiologists firmly believed until quite recently.

This past November, Peter S. Eriksson of the Sahlgrenska University Hospital in Goteborg, Sweden, one of us (Gage) at the Salk Institute for Biological Studies in La Jolla, Calif., and several colleagues published the startling news that the mature human brain does spawn neurons routinely in at least one site— the hippocampus, an area important to memory and learning. (The hippocampus is not where memories are stored, but it helps to form them after receiving input from other brain regions. People with hippocampal damage have difficulty acquiring knowledge yet can recall information learned before their injury.)

The absolute number of new cells is low relative to the total number in the brain. Nevertheless, considered with recent findings in animals, the November discovery raises some tantalising prospects for medicine. Current data suggest that stem cells probably make new neurons in another part of the human brain and also reside, albeit dormantly, in additional locations. Hence, the adult brain, which repairs itself so poorly, might actually harbor great potential for neuronal regeneration. If investigators can learn how to induce existing stem cells to produce useful numbers of functional nerve cells in chosen parts of the brain, that advance could make it possible to ease any number of disorders involving neuronal damage and death—among them Alzheimer's disease, Parkinson's disease and disabilities that accompany stroke and trauma.

 Although the finding that the mature human brain can generate neurons was surprising, hints had actually appeared for years in studies of other adult mammals. As long ago as 1965, for instance, Joseph Altman and Gopal D. Das of the Massachusetts Institute of Technology had described neuronal production (neurogenesis) in the hippocampus of adult rats—in the precise hippocampal area, known as the dentate gyrus, where it has now been found in human beings.

Early Hints ... and Doubts

Other studies subsequently confirmed Altman and Das's report, but most researchers did not view the data as evidence of significant neurogenesis in adult mammals or as an indication that even the human brain might have some regenerative potential. One reason was that the methods then available could not estimate accurately the number of neurons being born nor prove definitively that the new cells were neurons. Further, the concept of brain stem cells had not yet been introduced. Researchers therefore thought that for new nerve cells to appear, fully mature versions would have to replicate—an unbelievably difficult feat. Scientists also underestimated the relevance of the findings to the human brain in part because no one had yet uncovered clear evidence of neurogenesis in monkeys or apes, which are primates and thus are closer to humans genetically and physiologically than are other mammals.

There matters stood until the mid1980s, when Fernando Nottebohm of the Rockefeller University jarred the field with astonishing results in adult canaries. He discovered that neurogenesis occurred in brain centers responsible for song learning and, moreover, that the process accelerated during the seasons in which the adult birds acquired their songs. Nottebohm and his co-workers also showed that neuron formation in the hippocampus of adult chickadees rose during seasons that placed high demands on the birds' memory system, particularly when the animals had to keep track of increasingly dispersed food storage sites. Nottebohm's dramatic results led to a reawakening of interest in neurogenesis in adult mammals and of course caused investigators to ponder once more whether the mature human brain had any regenerative potential.

Optimism about the possibility of human neurogenesis was shortlived, however. At about the same time, Pasko Rakic and his associates at Yale University pioneered the study of neurogenesis in adult primates. That work, which was well done for its time, failed to find new brain neurons in grown rhesus monkeys.

Logic, too, continued to argue against neuronal birth in the adult human brain. Biologists knew that the extent of neurogenesis had become increasingly restricted throughout evolution, as the brain became more complex. Whereas lizards and other lower animals enjoy massive neuronal regeneration when their brains are damaged, mammals lack that robust response. It seemed reasonable to assume that the addition of neurons to the intricately wired human brain would threaten the orderly flow of signals along established pathways.

Signs that this reasoning might be flawed emerged only a few years ago. First, a team headed by Elizabeth Gould and Bruce S. McEwen of Rockefeller and Eberhard Fuchs of the German Primate Center in Gottingen revealed in 1997 that some neurogenesis occurs in the hippocampus of the primatelike tree shrew. Then, in March 1998, they found the same phenomenon in the marmoset. Marmoset monkeys are evolutionarily more distant from humans than rhesus monkeys are, but they are nonetheless primates.

Cancer Patients Showed the Way

Clearly, the question of whether humans possess a capacity for neuro genesis in adulthood could be resolved only by studying people directly. Yet such studies seemed impossible, because the methods applied to demonstrate new neuron formation in animals did not appear to be transferable to people.

Those techniques vary but usually take advantage of the fact that before cells divide, they duplicate their chromosomes, which enables each daughter cell to receive a full set. In the animal experiments, investigators typically inject subjects with a traceable material (a "marker") that will become integrated only into the DNA of cells preparing to divide. That marker becomes a part of the DNA in the resulting daughter cells and is then inherited by the daughters' daughters and by future descendants of the original dividing cells.

After a while, some of the marked cells differentiate—that is, they specialize, becoming specific kinds of neurons or glia (the other main class of cells in the brain). Having allowed time for differentiation to occur, workers remove the brain and cut it into thin sections. The sections are stained for the presence of neurons and glia and are viewed under a microscope. Cells that retain the marker (a sign of their derivation from the original dividing cells) and also have the anatomic and chemical characteristics of neurons can be assumed to have differentiated into nerve cells after the marker was introduced into the body. Fully differentiated neurons do not divide and cannot integrate the marker; they therefore show no signs of it.

Living humans obviously cannot be examined in this way. That obstacle seemed insurmountable until Eriksson hit on a solution soon after completing a sabbatical with our group at Salk. A clinician, he one day found himself on call with a cancer specialist. As the two chatted, Eriksson learned that the substance we had been using as our marker for dividing cells in animals—bromodeoxyuridine (BrdU)—was coincidentally being given to some terminally ill patients with cancer of the tongue or larynx. These patients were part of a study that injected the compound to monitor tumor growth.

Eriksson realized that if he could obtain the hippocampus of study participants who eventually died, analyses conducted at Salk could identify the neurons and see whether any of them displayed the DNA marker. The presence of BrdU would mean the affected neurons had formed after that substance was delivered. In other words, the study could prove that neurogenesis had occurred, presumably through stem cell proliferation and differentiation, during the patients' adulthood.

Eriksson obtained the patients' consent to investigate their brains after death. Between early 1996 and February 1998, he raced to the hospital and was given brain tissue from five such patients, who had passed away between the ages of 57 and 72. As hoped, all five brains displayed new neurons—specifically those known as granule cells—in the dentate gyrus. These patients donated their brains to this cause, and we owe this proof of adult human neurogenesis to their generosity. (Coincidentally, at about the time this study was published, Gould's and Rakic's groups both reported that nerve cell production does take place in the hippocampus of adult rhesus monkeys.)

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