University of Wisconsin neurobiologist Ronald Kalil was among those who pursued the question (15). His studies in young cats showed that entire networks of brain cells could be routed around damaged areas. Young animals whose primary vision centers were destroyed could still learn to see normally, he found, because cells in another part of their brains took up the job of processing vision. Yet, adult animals suffering the same destruction had no such luck (7). What was the difference?
Kalil finally determined that young animal brains are awash in chemicals called growth factors, while adult brains have far lower levels (11). He surmised that the abundance of growth factors helps the new brains organize themselves. When damage occurs, the growth factors simply start over and rebuild damaged networks. Adults have fewer growth factors because their brains, although they constantly undergo changes, are, for the most part, completed. All of which led to another question: Would adding extra growth factors prevent permanent damage in adult brains?
Soaking tiny sponges with a variety of growth factors, Kalil placed them inside newly damaged brain areas of adult cats. He and his colleagues found that these adult brains acted more like infant brains: Instead of suffering permanent damage, the adult brains repaired themselves. This ability of the brain to rewire itself, grow new parts for damaged cells, and even make new cells-its "plasticity," was thought to be impossible only a few years ago (4). Brain cells, medical students were taught, were hardwired like so many computer transistors. Once they burned out, that was the end.
Brain cells certainly could not sprout new communications lines to take over the jobs of nonfunctioning cells, it was said. Nor could they regenerate themselves after being hurt. Moreover, they absolutely could not divide to replenish the brain with new cells. All those "truths" are being tossed out as brain research undergoes a revolution fueled by molecular biology's remarkable ability to reveal the secrets of cells. Scientists now can hunt down and copy genes that govern cell reassembly and harness them for use in repairing damaged brains (3). The power of these tools was stunningly demonstrated with the discovery of a gene called NeuroD, which plays an essential role in the embryonic development of the brain and nervous system (6). So potent is this gene that when inserted into cells that normally would never become brain cells, it transforms them into brain cells. NeuroD not only opens the door to studying how brain cells are made, but it may make it possible to make new brain cells to replace those destroyed by Alzheimer's and other disorders. I find that this organ that seemed so inaccessible, that seemed as if it could not be repaired just a few short years ago, now appears to be monumentally plastic, and now we are beginning to take advantage of its healing powers.
The key to the brain's plasticity is a newly discovered family of chemicals, including nerve growth factor, that keep brain cells alive (11). They are called neurotrophic factors, from the Greek "neuro" for brain and "troph" for nourish (1). They have names like brain-derived growth factor, glial-derived growth factor, neurotrophic-3, and ciliary neurotrophic factor-simple titles that belie their lifesaving attributes. Neurotrophic factors are like nannies to brain cells. They are there when the cells are first born, making sure they are nourished, grow, and make the right connections. They are there throughout the life of the cells, guarding their health and repairing damage. Moreover, they are there to insure that the brain cells do the jobs they were created for, to learn and remember (12).
When neurotrophic factors decline or disappear, brain cells quickly fall down on the job, shrink and eventually die. This happens because the factors are no longer there to protect cells from being chopped up by free radicals, molecular piranhas created by normal body chemistry. Nor are the factors there to turn genes on and off to maintain the cells' communication lines or make sure the cells are sending out their "I'm okay, you're okay" messages to other cells.
The discovery of neurotrophic factors has opened the door to new generations of therapeutic agents that can revive sputtering brain cells, repair those that are damaged, rescue dying ones, and generate new cells. They hold the promise that we can correct neurologic problems that in the past were thought to be intractable. They may even hold the additional promise that we might be able to maintain neurologic function, which we thought always diminished with age (16). In addition, if we really want to be hopeful, I predict that we might even be able to provide a higher quality of life. That goal involves nothing less than the treatment and possible cure of such neurological scourges as Alzheimer's disease, Parkinson's, ALS, Huntington's, age-related memory loss, and stroke.
Glial-derived growth factor has been shown in laboratory tests to save brain cells that die in Parkinson's patients (13). Another growth factor, GM1 ganglioside, substantially reduced some of the functional impairments in Parkinson's patients, such as rigidity, tremors, and cognitive problems, according to the preliminary results of a pilot study (8). The growth factor, which was obtained from cow brains, appears to increase the brain's supply of dopamine.
Researchers reported the first proof that fetal tissue transplants survived, grew, and functioned in the brain of a Parkinson's patient (13). The transplant was linked to a significant improvement in the patient's condition, freeing him from the prison of rigidity and immobility, the main symptoms of the disease, and enabling him to enroll in an exercise class. However, the patient died from an unrelated cause. Scientists who examined his brain found that the transplanted tissue had been working. It is amazing how for the past fifteen years we have been trying to get to this point, to understand whether fetal transplants can work and how they work. The disease, which affects 500,000 Americans a year, is marked by a decline in the brain cells that make dopamine, a key neurotransmitter (14). Dopamine loss results in shaking, inability to move, and lack of body control.
Amyotrophic lateral sclerosis (ALS), also known s Lou Gehrig's disease, strikes 5,000 Americans a year and is characterized by muscle paralysis (17). The fatal disease appears to be linked to a decrease in neurotrophic factors that protect motor neurons from free-radical damage. The first success in slowing the devastating progressions of ALS has been achieved with insulin-like growth factor. IGF-1 supports the survival and regeneration of motor neurons (9). More encouraging work is under way for ALS. Studies suggest that injecting motor neurons that activate muscles with another factor, ciliary neurotrophic factor, may also slow progression of the disease (12). This neurotrophic factor seems to switch on genes that produce chemicals that neutralize free radicals.
Some neurotrophic factors are so powerful they can actually transform some body cells into brain cells. Cells taken from the inner core of adrenal glands, for instance, which sit atop the kidneys, normally make a tiny amount of dopamine. When mixed with nerve growth factor these adrenal cells change their shape, taking the form and function of brain cells. They sprout connections to nearby neurons and increase their production of dopamine, the neurotransmitter that declines in Parkinson's patients. A small number of cells are removed from a patient's adrenal glands, inserted into the brain through small holes in the skull, and then bathed in nerve growth factor for three weeks (5). A big advantage of this technique is that it avoids the risk of transplant rejection, since the cells are the patient's own.
Perking up the failing memories of Alzheimer's patients may be possible with genetically engineered skin cells (2). Memory could be restored in rats by inserting a gene that makes a protein essential for memory recovery into some of the animals' skin cells and then inserting the cells into their brains. The transplanted gene makes choline acetyltransferase, which turns choline into the neurotransmitter acetylcholine. It is the gradual decline of acetylcholine that causes Alzheimer's patients to lose their memory (1). This research is encouraging news for Alzheimer's disease treatment because it indicates that delivering a single neurotransmitter may provide memory improvement.
Although fetal tissue transplants have shown promise in treating brain disorders such as Parkinson's, many researchers would like to avoid the use of tissue from aborted fetuses. One alternative is to use a person's own skin or muscle cells. These cells can be bioengineered to carry growth factor genes, thus converting them into tiny factories from producing growth factors. Genetically engineered muscle cells to do the same thing were used, however, more simply by putting foreign genes into cells. It is called the "naked DNA" approach and consists of simply squirting bare DNA into cell cultures (10). The genes are absorbed into cells, by some still-unknown process, and start churning out copious amounts of growth factors.
This could be an outpatient procedure for Parkinson's and Alzheimer's patients. First, you take a muscle biopsy, grow the muscle cells in cultures with growth factor genes, and then a month later inject them into the brain under local anesthetic. Reflecting on these advances in brain research, it has only been in the last five years that the scientific community finally has some reason to be optimistic, thanks to molecular biology and the discovery of all these new growth factors.
1. Shooter, Eric. Neurotrophic factors. Boca Raton, FL: CRC Press, 1992. Pp. 25-34.
3. Brain Derived Neurotrophic Factor
4. Brain's plasticity
5. Cell Transplantation and Neurotrophic Mechanisms in Neurodegenerative Disorders
6. Development and NeuroD
7. Fetal Brain Damage, Developmental Delays and Intellectual Impairment
8. GM1 Gangliosidoses definition: Epidemiology: pathogenesis: 1
9. Insulin-like Growth Factors
10. JIMM The Immunologic Properties of DNA
11. Nerve Growth Factors
12. Neurotrophic Factors
13. Parkinson's Disease
14. Reactive oxygen species and dopamine uptake
15. Ronald Kalil
16. Structure, regulation and function of neurotrophic growth factors
17. What is ALS
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This paper reflects the research and thoughts of a student at the time the paper was written for a course at Bryn Mawr College. Like other materials on Serendip, it is not intended to be "authoritative" but rather to help others further develop their own explorations. Web links were active as of the time the paper was posted but are not updated.